CA3011306A1 - Cellular blend for the regeneration of chondrocytes or cartilage type cells - Google Patents
Cellular blend for the regeneration of chondrocytes or cartilage type cells Download PDFInfo
- Publication number
- CA3011306A1 CA3011306A1 CA3011306A CA3011306A CA3011306A1 CA 3011306 A1 CA3011306 A1 CA 3011306A1 CA 3011306 A CA3011306 A CA 3011306A CA 3011306 A CA3011306 A CA 3011306A CA 3011306 A1 CA3011306 A1 CA 3011306A1
- Authority
- CA
- Canada
- Prior art keywords
- cells
- individual
- gene product
- disc
- tie2
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 210000004027 cell Anatomy 0.000 title claims abstract description 214
- 239000000203 mixture Substances 0.000 title claims abstract description 62
- 210000000845 cartilage Anatomy 0.000 title claims description 26
- 210000001612 chondrocyte Anatomy 0.000 title claims description 16
- 230000008929 regeneration Effects 0.000 title description 13
- 238000011069 regeneration method Methods 0.000 title description 13
- 230000001413 cellular effect Effects 0.000 title description 5
- 238000000034 method Methods 0.000 claims abstract description 79
- 101100481408 Danio rerio tie2 gene Proteins 0.000 claims abstract description 33
- 101100481410 Mus musculus Tek gene Proteins 0.000 claims abstract description 33
- 210000002950 fibroblast Anatomy 0.000 claims abstract description 29
- 210000004623 platelet-rich plasma Anatomy 0.000 claims abstract description 29
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 27
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 19
- 239000003636 conditioned culture medium Substances 0.000 claims abstract description 18
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 16
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 15
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 15
- 230000001172 regenerating effect Effects 0.000 claims abstract description 6
- -1 Mef2C Proteins 0.000 claims description 72
- 101710137353 CCN family member 4 Proteins 0.000 claims description 23
- 108010039419 Connective Tissue Growth Factor Proteins 0.000 claims description 21
- 101150106167 SOX9 gene Proteins 0.000 claims description 19
- 102100031173 CCN family member 4 Human genes 0.000 claims description 17
- 101000934220 Homo sapiens CCN family member 5 Proteins 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 17
- 102100031168 CCN family member 2 Human genes 0.000 claims description 15
- 230000003412 degenerative effect Effects 0.000 claims description 15
- 102100036601 Aggrecan core protein Human genes 0.000 claims description 14
- 210000000130 stem cell Anatomy 0.000 claims description 14
- 102000008186 Collagen Human genes 0.000 claims description 12
- 108010035532 Collagen Proteins 0.000 claims description 12
- 229920001436 collagen Polymers 0.000 claims description 12
- 229940124597 therapeutic agent Drugs 0.000 claims description 12
- 108010067219 Aggrecans Proteins 0.000 claims description 11
- 102100025215 CCN family member 5 Human genes 0.000 claims description 11
- 210000001789 adipocyte Anatomy 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 11
- 108010072582 Matrilin Proteins Proteins 0.000 claims description 10
- 102000016611 Proteoglycans Human genes 0.000 claims description 10
- 108010067787 Proteoglycans Proteins 0.000 claims description 10
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 claims description 10
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 claims description 10
- 229940099456 transforming growth factor beta 1 Drugs 0.000 claims description 10
- 102100027995 Collagenase 3 Human genes 0.000 claims description 9
- 101000577887 Homo sapiens Collagenase 3 Proteins 0.000 claims description 9
- 238000000338 in vitro Methods 0.000 claims description 9
- 238000001727 in vivo Methods 0.000 claims description 9
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 8
- 102100024506 Bone morphogenetic protein 2 Human genes 0.000 claims description 7
- 206010021143 Hypoxia Diseases 0.000 claims description 7
- 101000762366 Homo sapiens Bone morphogenetic protein 2 Proteins 0.000 claims description 6
- 101150000629 TGFB1 gene Proteins 0.000 claims description 6
- 230000007954 hypoxia Effects 0.000 claims description 6
- 230000000735 allogeneic effect Effects 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 238000001514 detection method Methods 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 102100032912 CD44 antigen Human genes 0.000 claims description 4
- 102100028084 Hyaluronan and proteoglycan link protein 1 Human genes 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 150000003384 small molecules Chemical class 0.000 claims description 4
- XXQGYGJZNMSSFD-UHFFFAOYSA-N 2-[2-(dimethylcarbamoyl)phenoxy]acetic acid Chemical compound CN(C)C(=O)C1=CC=CC=C1OCC(O)=O XXQGYGJZNMSSFD-UHFFFAOYSA-N 0.000 claims description 3
- 102100033714 40S ribosomal protein S6 Human genes 0.000 claims description 3
- 108091005663 ADAMTS5 Proteins 0.000 claims description 3
- 102000051389 ADAMTS5 Human genes 0.000 claims description 3
- 102000051354 ADAMTS9 Human genes 0.000 claims description 3
- 108091005669 ADAMTS9 Proteins 0.000 claims description 3
- 108010016281 ADP-Ribosylation Factor 1 Proteins 0.000 claims description 3
- 102100034341 ADP-ribosylation factor 1 Human genes 0.000 claims description 3
- 102100032814 ATP-dependent zinc metalloprotease YME1L1 Human genes 0.000 claims description 3
- 108010080691 Alcohol O-acetyltransferase Proteins 0.000 claims description 3
- 108010003133 Aldo-Keto Reductase Family 1 Member C2 Proteins 0.000 claims description 3
- 102100024089 Aldo-keto reductase family 1 member C2 Human genes 0.000 claims description 3
- 108700024832 B-Cell CLL-Lymphoma 10 Proteins 0.000 claims description 3
- 102100037598 B-cell lymphoma/leukemia 10 Human genes 0.000 claims description 3
- 101150074953 BCL10 gene Proteins 0.000 claims description 3
- 102000017916 BDKRB1 Human genes 0.000 claims description 3
- 108060003359 BDKRB1 Proteins 0.000 claims description 3
- 108010040168 Bcl-2-Like Protein 11 Proteins 0.000 claims description 3
- 102000001765 Bcl-2-Like Protein 11 Human genes 0.000 claims description 3
- 102100022526 Bone morphogenetic protein 5 Human genes 0.000 claims description 3
- 102100022525 Bone morphogenetic protein 6 Human genes 0.000 claims description 3
- 102100031746 Bone sialoprotein 2 Human genes 0.000 claims description 3
- 102100022443 CXADR-like membrane protein Human genes 0.000 claims description 3
- 102100032146 Carbohydrate sulfotransferase 11 Human genes 0.000 claims description 3
- 102100038768 Carbohydrate sulfotransferase 3 Human genes 0.000 claims description 3
- 102100031192 Chondroitin sulfate N-acetylgalactosaminyltransferase 1 Human genes 0.000 claims description 3
- 102100028757 Chondroitin sulfate proteoglycan 4 Human genes 0.000 claims description 3
- 102100033601 Collagen alpha-1(I) chain Human genes 0.000 claims description 3
- 102100029136 Collagen alpha-1(II) chain Human genes 0.000 claims description 3
- 102100031611 Collagen alpha-1(III) chain Human genes 0.000 claims description 3
- 102100022145 Collagen alpha-1(IV) chain Human genes 0.000 claims description 3
- 102100040512 Collagen alpha-1(IX) chain Human genes 0.000 claims description 3
- 102100031457 Collagen alpha-1(V) chain Human genes 0.000 claims description 3
- 102100031519 Collagen alpha-1(VI) chain Human genes 0.000 claims description 3
- 102100024335 Collagen alpha-1(VII) chain Human genes 0.000 claims description 3
- 102100024337 Collagen alpha-1(VIII) chain Human genes 0.000 claims description 3
- 102100036217 Collagen alpha-1(X) chain Human genes 0.000 claims description 3
- 102100033825 Collagen alpha-1(XI) chain Human genes 0.000 claims description 3
- 102100027442 Collagen alpha-1(XII) chain Human genes 0.000 claims description 3
- 102100040993 Collagen alpha-1(XIII) chain Human genes 0.000 claims description 3
- 102100024203 Collagen alpha-1(XIV) chain Human genes 0.000 claims description 3
- 102100031161 Collagen alpha-1(XIX) chain Human genes 0.000 claims description 3
- 102100022640 Collagen alpha-1(XV) chain Human genes 0.000 claims description 3
- 102100028257 Collagen alpha-1(XVI) chain Human genes 0.000 claims description 3
- 102100028256 Collagen alpha-1(XVII) chain Human genes 0.000 claims description 3
- 102100031162 Collagen alpha-1(XVIII) chain Human genes 0.000 claims description 3
- 102100031160 Collagen alpha-1(XX) chain Human genes 0.000 claims description 3
- 102100040995 Collagen alpha-1(XXI) chain Human genes 0.000 claims description 3
- 102100037296 Collagen alpha-1(XXII) chain Human genes 0.000 claims description 3
- 102100030781 Collagen alpha-1(XXIII) chain Human genes 0.000 claims description 3
- 102100037285 Collagen alpha-1(XXIV) chain Human genes 0.000 claims description 3
- 102100031576 Collagen alpha-1(XXV) chain Human genes 0.000 claims description 3
- 102100028284 Collagen alpha-1(XXVI) chain Human genes 0.000 claims description 3
- 102100031544 Collagen alpha-1(XXVII) chain Human genes 0.000 claims description 3
- 102100029078 Collagen alpha-1(XXVIII) chain Human genes 0.000 claims description 3
- 102100036213 Collagen alpha-2(I) chain Human genes 0.000 claims description 3
- 102100033781 Collagen alpha-2(IV) chain Human genes 0.000 claims description 3
- 102100030976 Collagen alpha-2(IX) chain Human genes 0.000 claims description 3
- 102100031502 Collagen alpha-2(V) chain Human genes 0.000 claims description 3
- 102100031518 Collagen alpha-2(VI) chain Human genes 0.000 claims description 3
- 102100040496 Collagen alpha-2(VIII) chain Human genes 0.000 claims description 3
- 102100033885 Collagen alpha-2(XI) chain Human genes 0.000 claims description 3
- 102100033780 Collagen alpha-3(IV) chain Human genes 0.000 claims description 3
- 102100030977 Collagen alpha-3(IX) chain Human genes 0.000 claims description 3
- 102100031501 Collagen alpha-3(V) chain Human genes 0.000 claims description 3
- 102100024338 Collagen alpha-3(VI) chain Human genes 0.000 claims description 3
- 102100033779 Collagen alpha-4(IV) chain Human genes 0.000 claims description 3
- 102100033775 Collagen alpha-5(IV) chain Human genes 0.000 claims description 3
- 102100024344 Collagen alpha-5(VI) chain Human genes 0.000 claims description 3
- 102100033773 Collagen alpha-6(IV) chain Human genes 0.000 claims description 3
- 102100025890 Complement C1q tumor necrosis factor-related protein 3 Human genes 0.000 claims description 3
- 108010043471 Core Binding Factor Alpha 2 Subunit Proteins 0.000 claims description 3
- 102100028181 Cytokine-like protein 1 Human genes 0.000 claims description 3
- 102100036318 Cytoplasmic phosphatidylinositol transfer protein 1 Human genes 0.000 claims description 3
- 101001030219 Drosophila melanogaster Unconventional myosin ID Proteins 0.000 claims description 3
- 102000017914 EDNRA Human genes 0.000 claims description 3
- 102100032449 EGF-like repeat and discoidin I-like domain-containing protein 3 Human genes 0.000 claims description 3
- 102100029994 ERO1-like protein alpha Human genes 0.000 claims description 3
- 102100021473 Electrogenic sodium bicarbonate cotransporter 4 Human genes 0.000 claims description 3
- 102100025471 Epiphycan Human genes 0.000 claims description 3
- 102100033175 Ethanolamine kinase 1 Human genes 0.000 claims description 3
- 102100036762 Extended synaptotagmin-2 Human genes 0.000 claims description 3
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 claims description 3
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 claims description 3
- 102100037362 Fibronectin Human genes 0.000 claims description 3
- 102100026545 Fibronectin type III domain-containing protein 3B Human genes 0.000 claims description 3
- 102000004315 Forkhead Transcription Factors Human genes 0.000 claims description 3
- 108090000852 Forkhead Transcription Factors Proteins 0.000 claims description 3
- 102000003817 Fos-related antigen 1 Human genes 0.000 claims description 3
- 108090000123 Fos-related antigen 1 Proteins 0.000 claims description 3
- 102100021261 Frizzled-10 Human genes 0.000 claims description 3
- 102100025614 Galectin-related protein Human genes 0.000 claims description 3
- 102100033295 Glial cell line-derived neurotrophic factor Human genes 0.000 claims description 3
- 102100036596 Glutamyl-tRNA(Gln) amidotransferase subunit B, mitochondrial Human genes 0.000 claims description 3
- 102100021194 Glypican-6 Human genes 0.000 claims description 3
- 102100027711 Histone-lysine N-methyltransferase SETD5 Human genes 0.000 claims description 3
- 102100028091 Homeobox protein Nkx-3.2 Human genes 0.000 claims description 3
- 101000656896 Homo sapiens 40S ribosomal protein S6 Proteins 0.000 claims description 3
- 101000899388 Homo sapiens Bone morphogenetic protein 5 Proteins 0.000 claims description 3
- 101000899390 Homo sapiens Bone morphogenetic protein 6 Proteins 0.000 claims description 3
- 101000707248 Homo sapiens Bone sialoprotein 2 Proteins 0.000 claims description 3
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 claims description 3
- 101000775587 Homo sapiens Carbohydrate sulfotransferase 11 Proteins 0.000 claims description 3
- 101000882992 Homo sapiens Carbohydrate sulfotransferase 3 Proteins 0.000 claims description 3
- 101000776615 Homo sapiens Chondroitin sulfate N-acetylgalactosaminyltransferase 1 Proteins 0.000 claims description 3
- 101000916489 Homo sapiens Chondroitin sulfate proteoglycan 4 Proteins 0.000 claims description 3
- 101000771163 Homo sapiens Collagen alpha-1(II) chain Proteins 0.000 claims description 3
- 101000993285 Homo sapiens Collagen alpha-1(III) chain Proteins 0.000 claims description 3
- 101000901150 Homo sapiens Collagen alpha-1(IV) chain Proteins 0.000 claims description 3
- 101000749901 Homo sapiens Collagen alpha-1(IX) chain Proteins 0.000 claims description 3
- 101000941708 Homo sapiens Collagen alpha-1(V) chain Proteins 0.000 claims description 3
- 101000941581 Homo sapiens Collagen alpha-1(VI) chain Proteins 0.000 claims description 3
- 101000909498 Homo sapiens Collagen alpha-1(VII) chain Proteins 0.000 claims description 3
- 101000909492 Homo sapiens Collagen alpha-1(VIII) chain Proteins 0.000 claims description 3
- 101000875027 Homo sapiens Collagen alpha-1(X) chain Proteins 0.000 claims description 3
- 101000710623 Homo sapiens Collagen alpha-1(XI) chain Proteins 0.000 claims description 3
- 101000861874 Homo sapiens Collagen alpha-1(XII) chain Proteins 0.000 claims description 3
- 101000749004 Homo sapiens Collagen alpha-1(XIII) chain Proteins 0.000 claims description 3
- 101000909626 Homo sapiens Collagen alpha-1(XIV) chain Proteins 0.000 claims description 3
- 101000940120 Homo sapiens Collagen alpha-1(XIX) chain Proteins 0.000 claims description 3
- 101000899935 Homo sapiens Collagen alpha-1(XV) chain Proteins 0.000 claims description 3
- 101000860648 Homo sapiens Collagen alpha-1(XVI) chain Proteins 0.000 claims description 3
- 101000860679 Homo sapiens Collagen alpha-1(XVII) chain Proteins 0.000 claims description 3
- 101000940068 Homo sapiens Collagen alpha-1(XVIII) chain Proteins 0.000 claims description 3
- 101000940122 Homo sapiens Collagen alpha-1(XX) chain Proteins 0.000 claims description 3
- 101000748976 Homo sapiens Collagen alpha-1(XXI) chain Proteins 0.000 claims description 3
- 101000952998 Homo sapiens Collagen alpha-1(XXII) chain Proteins 0.000 claims description 3
- 101000920176 Homo sapiens Collagen alpha-1(XXIII) chain Proteins 0.000 claims description 3
- 101000952969 Homo sapiens Collagen alpha-1(XXIV) chain Proteins 0.000 claims description 3
- 101000940250 Homo sapiens Collagen alpha-1(XXV) chain Proteins 0.000 claims description 3
- 101000860862 Homo sapiens Collagen alpha-1(XXVI) chain Proteins 0.000 claims description 3
- 101000940372 Homo sapiens Collagen alpha-1(XXVII) chain Proteins 0.000 claims description 3
- 101000770661 Homo sapiens Collagen alpha-1(XXVIII) chain Proteins 0.000 claims description 3
- 101000875067 Homo sapiens Collagen alpha-2(I) chain Proteins 0.000 claims description 3
- 101000710876 Homo sapiens Collagen alpha-2(IV) chain Proteins 0.000 claims description 3
- 101000919645 Homo sapiens Collagen alpha-2(IX) chain Proteins 0.000 claims description 3
- 101000941594 Homo sapiens Collagen alpha-2(V) chain Proteins 0.000 claims description 3
- 101000941585 Homo sapiens Collagen alpha-2(VI) chain Proteins 0.000 claims description 3
- 101000749886 Homo sapiens Collagen alpha-2(VIII) chain Proteins 0.000 claims description 3
- 101000710619 Homo sapiens Collagen alpha-2(XI) chain Proteins 0.000 claims description 3
- 101000710873 Homo sapiens Collagen alpha-3(IV) chain Proteins 0.000 claims description 3
- 101000919644 Homo sapiens Collagen alpha-3(IX) chain Proteins 0.000 claims description 3
- 101000941596 Homo sapiens Collagen alpha-3(V) chain Proteins 0.000 claims description 3
- 101000909506 Homo sapiens Collagen alpha-3(VI) chain Proteins 0.000 claims description 3
- 101000710870 Homo sapiens Collagen alpha-4(IV) chain Proteins 0.000 claims description 3
- 101000710886 Homo sapiens Collagen alpha-5(IV) chain Proteins 0.000 claims description 3
- 101000909508 Homo sapiens Collagen alpha-5(VI) chain Proteins 0.000 claims description 3
- 101000710885 Homo sapiens Collagen alpha-6(IV) chain Proteins 0.000 claims description 3
- 101000933673 Homo sapiens Complement C1q tumor necrosis factor-related protein 3 Proteins 0.000 claims description 3
- 101000916671 Homo sapiens Cytokine-like protein 1 Proteins 0.000 claims description 3
- 101001074657 Homo sapiens Cytoplasmic phosphatidylinositol transfer protein 1 Proteins 0.000 claims description 3
- 101001016381 Homo sapiens EGF-like repeat and discoidin I-like domain-containing protein 3 Proteins 0.000 claims description 3
- 101001010853 Homo sapiens ERO1-like protein alpha Proteins 0.000 claims description 3
- 101000967336 Homo sapiens Endothelin-1 receptor Proteins 0.000 claims description 3
- 101001056751 Homo sapiens Epiphycan Proteins 0.000 claims description 3
- 101000851032 Homo sapiens Ethanolamine kinase 1 Proteins 0.000 claims description 3
- 101000851521 Homo sapiens Extended synaptotagmin-2 Proteins 0.000 claims description 3
- 101001027128 Homo sapiens Fibronectin Proteins 0.000 claims description 3
- 101000913642 Homo sapiens Fibronectin type III domain-containing protein 3B Proteins 0.000 claims description 3
- 101000819451 Homo sapiens Frizzled-10 Proteins 0.000 claims description 3
- 101001004750 Homo sapiens Galectin-related protein Proteins 0.000 claims description 3
- 101001073064 Homo sapiens Glutamyl-tRNA(Gln) amidotransferase subunit B, mitochondrial Proteins 0.000 claims description 3
- 101001040704 Homo sapiens Glypican-6 Proteins 0.000 claims description 3
- 101000650669 Homo sapiens Histone-lysine N-methyltransferase SETD5 Proteins 0.000 claims description 3
- 101000578251 Homo sapiens Homeobox protein Nkx-3.2 Proteins 0.000 claims description 3
- 101000596925 Homo sapiens Homeobox protein TGIF1 Proteins 0.000 claims description 3
- 101001079904 Homo sapiens Hyaluronan and proteoglycan link protein 1 Proteins 0.000 claims description 3
- 101000839066 Homo sapiens Hypoxia-inducible lipid droplet-associated protein Proteins 0.000 claims description 3
- 101000902205 Homo sapiens Inactive cytidine monophosphate-N-acetylneuraminic acid hydroxylase Proteins 0.000 claims description 3
- 101000998783 Homo sapiens Insulin-like 3 Proteins 0.000 claims description 3
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 claims description 3
- 101000840566 Homo sapiens Insulin-like growth factor-binding protein 5 Proteins 0.000 claims description 3
- 101001078149 Homo sapiens Integrin alpha-10 Proteins 0.000 claims description 3
- 101000935043 Homo sapiens Integrin beta-1 Proteins 0.000 claims description 3
- 101000852255 Homo sapiens Interleukin-1 receptor-associated kinase-like 2 Proteins 0.000 claims description 3
- 101001033233 Homo sapiens Interleukin-10 Proteins 0.000 claims description 3
- 101001139117 Homo sapiens Krueppel-like factor 7 Proteins 0.000 claims description 3
- 101000874532 Homo sapiens Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase Proteins 0.000 claims description 3
- 101000749842 Homo sapiens Leukocyte cell-derived chemotaxin 1 Proteins 0.000 claims description 3
- 101000984624 Homo sapiens Low-density lipoprotein receptor-related protein 11 Proteins 0.000 claims description 3
- 101001025945 Homo sapiens Lysine-specific demethylase 7A Proteins 0.000 claims description 3
- 101001043351 Homo sapiens Lysyl oxidase homolog 4 Proteins 0.000 claims description 3
- 101000577881 Homo sapiens Macrophage metalloelastase Proteins 0.000 claims description 3
- 101001011906 Homo sapiens Matrix metalloproteinase-14 Proteins 0.000 claims description 3
- 101001011886 Homo sapiens Matrix metalloproteinase-16 Proteins 0.000 claims description 3
- 101000973510 Homo sapiens Melanoma-derived growth regulatory protein Proteins 0.000 claims description 3
- 101001018298 Homo sapiens Microtubule-associated serine/threonine-protein kinase 4 Proteins 0.000 claims description 3
- 101000624898 Homo sapiens Myb/SANT-like DNA-binding domain-containing protein 3 Proteins 0.000 claims description 3
- 101000650160 Homo sapiens NEDD4-like E3 ubiquitin-protein ligase WWP2 Proteins 0.000 claims description 3
- 101001124991 Homo sapiens Nitric oxide synthase, inducible Proteins 0.000 claims description 3
- 101001121636 Homo sapiens Nucleoporin p58/p45 Proteins 0.000 claims description 3
- 101000586302 Homo sapiens Oncostatin-M-specific receptor subunit beta Proteins 0.000 claims description 3
- 101000988395 Homo sapiens PDZ and LIM domain protein 4 Proteins 0.000 claims description 3
- 101000600766 Homo sapiens Podoplanin Proteins 0.000 claims description 3
- 101000829538 Homo sapiens Polypeptide N-acetylgalactosaminyltransferase 15 Proteins 0.000 claims description 3
- 101000944000 Homo sapiens Potassium channel subfamily T member 2 Proteins 0.000 claims description 3
- 101000914035 Homo sapiens Pre-mRNA-splicing regulator WTAP Proteins 0.000 claims description 3
- 101000579300 Homo sapiens Prostaglandin F2-alpha receptor Proteins 0.000 claims description 3
- 101000875518 Homo sapiens Protein FAM110B Proteins 0.000 claims description 3
- 101000781981 Homo sapiens Protein Wnt-11 Proteins 0.000 claims description 3
- 101000780643 Homo sapiens Protein argonaute-2 Proteins 0.000 claims description 3
- 101001072492 Homo sapiens RAB6-interacting golgin Proteins 0.000 claims description 3
- 101001112424 Homo sapiens RB1-inducible coiled-coil protein 1 Proteins 0.000 claims description 3
- 101001103597 Homo sapiens RING finger protein 24 Proteins 0.000 claims description 3
- 101000591128 Homo sapiens RNA-binding protein Musashi homolog 2 Proteins 0.000 claims description 3
- 101000581125 Homo sapiens Rho-related GTP-binding protein RhoF Proteins 0.000 claims description 3
- 101000666657 Homo sapiens Rho-related GTP-binding protein RhoQ Proteins 0.000 claims description 3
- 101000945090 Homo sapiens Ribosomal protein S6 kinase alpha-3 Proteins 0.000 claims description 3
- 101000739671 Homo sapiens Semaphorin-6D Proteins 0.000 claims description 3
- 101000644537 Homo sapiens Sequestosome-1 Proteins 0.000 claims description 3
- 101000604981 Homo sapiens Serine beta-lactamase-like protein LACTB, mitochondrial Proteins 0.000 claims description 3
- 101000654491 Homo sapiens Serine/threonine-protein kinase SIK3 Proteins 0.000 claims description 3
- 101000780111 Homo sapiens Serine/threonine-protein phosphatase 6 regulatory ankyrin repeat subunit A Proteins 0.000 claims description 3
- 101000688667 Homo sapiens Sideroflexin-3 Proteins 0.000 claims description 3
- 101000631711 Homo sapiens Signal peptide, CUB and EGF-like domain-containing protein 3 Proteins 0.000 claims description 3
- 101000665020 Homo sapiens Sorting nexin-5 Proteins 0.000 claims description 3
- 101000990915 Homo sapiens Stromelysin-1 Proteins 0.000 claims description 3
- 101000826406 Homo sapiens Sulfotransferase 1C2 Proteins 0.000 claims description 3
- 101000585332 Homo sapiens Sulfotransferase 1C4 Proteins 0.000 claims description 3
- 101000801287 Homo sapiens Tenomodulin Proteins 0.000 claims description 3
- 101000633608 Homo sapiens Thrombospondin-3 Proteins 0.000 claims description 3
- 101000708741 Homo sapiens Transcription factor RelB Proteins 0.000 claims description 3
- 101000642512 Homo sapiens Transcription factor SOX-5 Proteins 0.000 claims description 3
- 101000610609 Homo sapiens Tumor necrosis factor receptor superfamily member 10D Proteins 0.000 claims description 3
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 claims description 3
- 101000874518 Homo sapiens UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 7 Proteins 0.000 claims description 3
- 101000768621 Homo sapiens UHRF1-binding protein 1-like Proteins 0.000 claims description 3
- 101000607320 Homo sapiens UL16-binding protein 2 Proteins 0.000 claims description 3
- 101000760210 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 12 Proteins 0.000 claims description 3
- 101000643925 Homo sapiens Ubiquitin-fold modifier 1 Proteins 0.000 claims description 3
- 101000772964 Homo sapiens Ubiquitin-protein ligase E3C Proteins 0.000 claims description 3
- 101000841490 Homo sapiens Unique cartilage matrix-associated protein Proteins 0.000 claims description 3
- 101000750267 Homo sapiens Vasorin Proteins 0.000 claims description 3
- 101000965719 Homo sapiens Volume-regulated anion channel subunit LRRC8C Proteins 0.000 claims description 3
- 101000788853 Homo sapiens Zinc finger CCHC domain-containing protein 7 Proteins 0.000 claims description 3
- 101000759188 Homo sapiens Zinc finger FYVE domain-containing protein 16 Proteins 0.000 claims description 3
- 101000964584 Homo sapiens Zinc finger protein 160 Proteins 0.000 claims description 3
- 101000857276 Homo sapiens Zinc finger protein GLIS3 Proteins 0.000 claims description 3
- 101000721407 Homo sapiens Zinc finger protein OZF Proteins 0.000 claims description 3
- 101000853444 Homo sapiens Zinc finger protein Rlf Proteins 0.000 claims description 3
- 101000772560 Homo sapiens Zinc finger transcription factor Trps1 Proteins 0.000 claims description 3
- 108090000320 Hyaluronan Synthases Proteins 0.000 claims description 3
- 102000003918 Hyaluronan Synthases Human genes 0.000 claims description 3
- 102100028891 Hypoxia-inducible lipid droplet-associated protein Human genes 0.000 claims description 3
- 102100022247 Inactive cytidine monophosphate-N-acetylneuraminic acid hydroxylase Human genes 0.000 claims description 3
- 102100033262 Insulin-like 3 Human genes 0.000 claims description 3
- 102100037852 Insulin-like growth factor I Human genes 0.000 claims description 3
- 102100029225 Insulin-like growth factor-binding protein 5 Human genes 0.000 claims description 3
- 102100025310 Integrin alpha-10 Human genes 0.000 claims description 3
- 102100025304 Integrin beta-1 Human genes 0.000 claims description 3
- 102100036433 Interleukin-1 receptor-associated kinase-like 2 Human genes 0.000 claims description 3
- 102100039068 Interleukin-10 Human genes 0.000 claims description 3
- 102100020692 Krueppel-like factor 7 Human genes 0.000 claims description 3
- 102100035655 Lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase Human genes 0.000 claims description 3
- 102100040448 Leukocyte cell-derived chemotaxin 1 Human genes 0.000 claims description 3
- 102100027119 Low-density lipoprotein receptor-related protein 11 Human genes 0.000 claims description 3
- 102100037465 Lysine-specific demethylase 7A Human genes 0.000 claims description 3
- 102000004137 Lysophosphatidic Acid Receptors Human genes 0.000 claims description 3
- 108090000642 Lysophosphatidic Acid Receptors Proteins 0.000 claims description 3
- 102100021968 Lysyl oxidase homolog 4 Human genes 0.000 claims description 3
- 102000003626 MCOLN2 Human genes 0.000 claims description 3
- 102100027998 Macrophage metalloelastase Human genes 0.000 claims description 3
- 102100030216 Matrix metalloproteinase-14 Human genes 0.000 claims description 3
- 102100030200 Matrix metalloproteinase-16 Human genes 0.000 claims description 3
- 101150056690 Mcoln2 gene Proteins 0.000 claims description 3
- 102100022185 Melanoma-derived growth regulatory protein Human genes 0.000 claims description 3
- 102100033252 Microtubule-associated serine/threonine-protein kinase 4 Human genes 0.000 claims description 3
- 101100490437 Mus musculus Acvrl1 gene Proteins 0.000 claims description 3
- 101100496563 Mus musculus Col6a4 gene Proteins 0.000 claims description 3
- 102100023254 Myb/SANT-like DNA-binding domain-containing protein 3 Human genes 0.000 claims description 3
- 102100027549 NEDD4-like E3 ubiquitin-protein ligase WWP2 Human genes 0.000 claims description 3
- 102000003729 Neprilysin Human genes 0.000 claims description 3
- 108090000028 Neprilysin Proteins 0.000 claims description 3
- 108090000770 Neuropilin-2 Proteins 0.000 claims description 3
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 claims description 3
- 102100025794 Nucleoporin p58/p45 Human genes 0.000 claims description 3
- 102100030098 Oncostatin-M-specific receptor subunit beta Human genes 0.000 claims description 3
- 102100029178 PDZ and LIM domain protein 4 Human genes 0.000 claims description 3
- 102100037265 Podoplanin Human genes 0.000 claims description 3
- 102100023229 Polypeptide N-acetylgalactosaminyltransferase 15 Human genes 0.000 claims description 3
- 102100033524 Potassium channel subfamily T member 2 Human genes 0.000 claims description 3
- 102100026431 Pre-mRNA-splicing regulator WTAP Human genes 0.000 claims description 3
- 102100028248 Prostaglandin F2-alpha receptor Human genes 0.000 claims description 3
- 102100035978 Protein FAM110B Human genes 0.000 claims description 3
- 102100036567 Protein Wnt-11 Human genes 0.000 claims description 3
- 102100034207 Protein argonaute-2 Human genes 0.000 claims description 3
- 102100034433 Protein kinase C-binding protein NELL2 Human genes 0.000 claims description 3
- 102100036699 RAB6-interacting golgin Human genes 0.000 claims description 3
- 102100023588 RB1-inducible coiled-coil protein 1 Human genes 0.000 claims description 3
- 102100039516 RING finger protein 24 Human genes 0.000 claims description 3
- 102100034027 RNA-binding protein Musashi homolog 2 Human genes 0.000 claims description 3
- 102100027608 Rho-related GTP-binding protein RhoF Human genes 0.000 claims description 3
- 102100038339 Rho-related GTP-binding protein RhoQ Human genes 0.000 claims description 3
- 102100033643 Ribosomal protein S6 kinase alpha-3 Human genes 0.000 claims description 3
- 102100025373 Runt-related transcription factor 1 Human genes 0.000 claims description 3
- 108091006419 SLC25A12 Proteins 0.000 claims description 3
- 108091006985 SLC41A2 Proteins 0.000 claims description 3
- 108091006261 SLC4A5 Proteins 0.000 claims description 3
- 102100037356 SLIT-ROBO Rho GTPase-activating protein 1 Human genes 0.000 claims description 3
- 102100037548 Semaphorin-6D Human genes 0.000 claims description 3
- 102100020814 Sequestosome-1 Human genes 0.000 claims description 3
- 102100038230 Serine beta-lactamase-like protein LACTB, mitochondrial Human genes 0.000 claims description 3
- 102100031445 Serine/threonine-protein kinase SIK3 Human genes 0.000 claims description 3
- 102100034285 Serine/threonine-protein phosphatase 6 regulatory ankyrin repeat subunit A Human genes 0.000 claims description 3
- 102100024226 Sideroflexin-3 Human genes 0.000 claims description 3
- 102100028925 Signal peptide, CUB and EGF-like domain-containing protein 3 Human genes 0.000 claims description 3
- 102100037196 Solute carrier family 41 member 2 Human genes 0.000 claims description 3
- 102100038624 Sorting nexin-5 Human genes 0.000 claims description 3
- 101150117830 Sox5 gene Proteins 0.000 claims description 3
- 101150066728 Srgap1 gene Proteins 0.000 claims description 3
- 102100030416 Stromelysin-1 Human genes 0.000 claims description 3
- 102100023985 Sulfotransferase 1C2 Human genes 0.000 claims description 3
- 102100033740 Tenomodulin Human genes 0.000 claims description 3
- 102100029524 Thrombospondin-3 Human genes 0.000 claims description 3
- 102100032727 Transcription factor RelB Human genes 0.000 claims description 3
- 102100036692 Transcription factor SOX-5 Human genes 0.000 claims description 3
- 102100040110 Tumor necrosis factor receptor superfamily member 10D Human genes 0.000 claims description 3
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 claims description 3
- 102000056723 UBE3C Human genes 0.000 claims description 3
- 102100035626 UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 7 Human genes 0.000 claims description 3
- 102100027977 UHRF1-binding protein 1-like Human genes 0.000 claims description 3
- 102100039989 UL16-binding protein 2 Human genes 0.000 claims description 3
- 102100024662 Ubiquitin carboxyl-terminal hydrolase 12 Human genes 0.000 claims description 3
- 102100021012 Ubiquitin-fold modifier 1 Human genes 0.000 claims description 3
- 102100029162 Unique cartilage matrix-associated protein Human genes 0.000 claims description 3
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 3
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 3
- 102100021161 Vasorin Human genes 0.000 claims description 3
- 102100040984 Volume-regulated anion channel subunit LRRC8C Human genes 0.000 claims description 3
- 108091009222 YME1L1 Proteins 0.000 claims description 3
- 102100025395 Zinc finger CCHC domain-containing protein 7 Human genes 0.000 claims description 3
- 102100023385 Zinc finger FYVE domain-containing protein 16 Human genes 0.000 claims description 3
- 102100040815 Zinc finger protein 160 Human genes 0.000 claims description 3
- 102100025879 Zinc finger protein GLIS3 Human genes 0.000 claims description 3
- 102100025229 Zinc finger protein OZF Human genes 0.000 claims description 3
- 102100030619 Zinc finger transcription factor Trps1 Human genes 0.000 claims description 3
- 108010029483 alpha 1 Chain Collagen Type I Proteins 0.000 claims description 3
- 239000012530 fluid Substances 0.000 claims description 3
- 101150003286 gata4 gene Proteins 0.000 claims description 3
- 210000003458 notochord Anatomy 0.000 claims description 3
- 101150055666 sox6 gene Proteins 0.000 claims description 3
- 102000000580 synaptojanin Human genes 0.000 claims description 3
- 108010016910 synaptojanin Proteins 0.000 claims description 3
- 101150115978 tbx5 gene Proteins 0.000 claims description 3
- 102100038509 E3 ubiquitin-protein ligase ARIH1 Human genes 0.000 claims description 2
- 101000808922 Homo sapiens E3 ubiquitin-protein ligase ARIH1 Proteins 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000007907 direct compression Methods 0.000 claims description 2
- 230000002706 hydrostatic effect Effects 0.000 claims description 2
- 238000003780 insertion Methods 0.000 claims description 2
- 230000037431 insertion Effects 0.000 claims description 2
- 101000635938 Homo sapiens Transforming growth factor beta-1 proprotein Proteins 0.000 claims 4
- 102100030742 Transforming growth factor beta-1 proprotein Human genes 0.000 claims 4
- 102100033668 Cartilage matrix protein Human genes 0.000 claims 1
- 102100033299 Glia-derived nexin Human genes 0.000 claims 1
- 101000997803 Homo sapiens Glia-derived nexin Proteins 0.000 claims 1
- 102100033670 Matrilin-3 Human genes 0.000 claims 1
- 102100033689 Matrilin-4 Human genes 0.000 claims 1
- 102100037984 Mitoferrin-1 Human genes 0.000 claims 1
- 108091006469 SLC25A37 Proteins 0.000 claims 1
- 108091006531 SLC28A3 Proteins 0.000 claims 1
- 102100021470 Solute carrier family 28 member 3 Human genes 0.000 claims 1
- 102100032891 Superoxide dismutase [Mn], mitochondrial Human genes 0.000 claims 1
- 108010045815 superoxide dismutase 2 Proteins 0.000 claims 1
- 101000711846 Homo sapiens Transcription factor SOX-9 Proteins 0.000 abstract 1
- 102100034204 Transcription factor SOX-9 Human genes 0.000 abstract 1
- 210000001519 tissue Anatomy 0.000 description 21
- 206010061246 Intervertebral disc degeneration Diseases 0.000 description 15
- 102100022014 Angiopoietin-1 receptor Human genes 0.000 description 14
- 230000008439 repair process Effects 0.000 description 14
- 230000001225 therapeutic effect Effects 0.000 description 10
- 101000753291 Homo sapiens Angiopoietin-1 receptor Proteins 0.000 description 9
- 208000018180 degenerative disc disease Diseases 0.000 description 9
- 208000021600 intervertebral disc degenerative disease Diseases 0.000 description 9
- 102000055008 Matrilin Proteins Human genes 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 6
- 101710131689 Angiopoietin-1 receptor Proteins 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 230000004069 differentiation Effects 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 208000002193 Pain Diseases 0.000 description 4
- 210000001188 articular cartilage Anatomy 0.000 description 4
- 210000000988 bone and bone Anatomy 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 102000000503 Collagen Type II Human genes 0.000 description 3
- 108010041390 Collagen Type II Proteins 0.000 description 3
- 208000008930 Low Back Pain Diseases 0.000 description 3
- 230000003848 cartilage regeneration Effects 0.000 description 3
- 230000024245 cell differentiation Effects 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 238000010899 nucleation Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 239000013598 vector Substances 0.000 description 3
- 229920000936 Agarose Polymers 0.000 description 2
- 208000008035 Back Pain Diseases 0.000 description 2
- 208000003618 Intervertebral Disc Displacement Diseases 0.000 description 2
- 206010050296 Intervertebral disc protrusion Diseases 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 208000007103 Spondylolisthesis Diseases 0.000 description 2
- 230000000386 athletic effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000002500 effect on skin Effects 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 210000002414 leg Anatomy 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 231100000862 numbness Toxicity 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 239000004633 polyglycolic acid Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- 102100036597 Basement membrane-specific heparan sulfate proteoglycan core protein Human genes 0.000 description 1
- 108010049931 Bone Morphogenetic Protein 2 Proteins 0.000 description 1
- 101001065614 Bos taurus Lumican Proteins 0.000 description 1
- 108091016585 CD44 antigen Proteins 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 108010059480 Chondroitin Sulfate Proteoglycans Proteins 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010090290 Growth Differentiation Factor 2 Proteins 0.000 description 1
- 102100040892 Growth/differentiation factor 2 Human genes 0.000 description 1
- 229920002971 Heparan sulfate Polymers 0.000 description 1
- 101710191341 Hyaluronan and proteoglycan link protein 1 Proteins 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 101100096242 Mus musculus Sox9 gene Proteins 0.000 description 1
- 108010018525 NFATC Transcription Factors Proteins 0.000 description 1
- 102000002673 NFATC Transcription Factors Human genes 0.000 description 1
- 206010033425 Pain in extremity Diseases 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 208000008765 Sciatica Diseases 0.000 description 1
- 108091027967 Small hairpin RNA Proteins 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 108090000054 Syndecan-2 Proteins 0.000 description 1
- 101710186513 Tyrosine-protein kinase receptor Tie-2 Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000000560 biocompatible material Substances 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000003592 biomimetic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000001217 buttock Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000002659 cell therapy Methods 0.000 description 1
- 230000004635 cellular health Effects 0.000 description 1
- 230000009816 chondrogenic differentiation Effects 0.000 description 1
- 229940059329 chondroitin sulfate Drugs 0.000 description 1
- 229960005188 collagen Drugs 0.000 description 1
- 239000000515 collagen sponge Substances 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Substances OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 238000011540 hip replacement Methods 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 210000005067 joint tissue Anatomy 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 238000013150 knee replacement Methods 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 206010025005 lumbar spinal stenosis Diseases 0.000 description 1
- 210000004705 lumbosacral region Anatomy 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 108091070501 miRNA Proteins 0.000 description 1
- 239000002679 microRNA Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229920000620 organic polymer Polymers 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 108010049224 perlecan Proteins 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 210000000273 spinal nerve root Anatomy 0.000 description 1
- 208000005198 spinal stenosis Diseases 0.000 description 1
- 208000001413 spine osteoarthritis Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
- C12N5/0655—Chondrocytes; Cartilage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/32—Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/16—Blood plasma; Blood serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/19—Platelets; Megacaryocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/33—Fibroblasts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/35—Fat tissue; Adipocytes; Stromal cells; Connective tissues
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/60—Transcription factors
Abstract
The present disclosure concerns at least methods and compositions for repairing and/or regenerating a disc of an individual in need thereof. In certain embodiments, an individual that is known to have or suspected to have or at risk for having a degenerated disc is provided a therapeutically effective amount of nucleus pulposus cells, one or more components from the nucleus pulposus, conditioned medium generated from nucleus pulposus cells, and additionally may also be provided fibroblasts, platelet rich plasma (PRP), SOX9 (protein or nucleic acid), and/or Tie2+ cells, for example.
Description
CELLULAR BLEND FOR THE REGENERATION OF CHONDROCYTES OR
CARTILAGE TYPE CELLS
[00011 This application claims priority to U.S. Provisional Patent Application Serial No. 62/278,635, filed January 14, 2016, and to U.S. Provisional Patent Application Serial No. 62/413,587, filed October 27, 2016, both of which applications are incorporated by reference herein in their entirety.
TECHNICAL FIELD
CARTILAGE TYPE CELLS
[00011 This application claims priority to U.S. Provisional Patent Application Serial No. 62/278,635, filed January 14, 2016, and to U.S. Provisional Patent Application Serial No. 62/413,587, filed October 27, 2016, both of which applications are incorporated by reference herein in their entirety.
TECHNICAL FIELD
[0002] The present invention generally concerns at least the fields of medicine, surgery, anatomy, biology, cell biology, and/or molecular biology. In particular aspects, the present invention concerns the fields of spinal disc repair. More particularly, the field of the invention concerns using a cell therapy for the regeneration of chondrocytes or other cartilage type cells.
BACKGROUND
BACKGROUND
[0003] Typically, cartilage is a tissue that is not naturally regenerated once damaged. Recently, efforts have been made to reconstruct damaged biological tissues by regenerating a portion of the damaged tissues in laboratories. This approach, defined as "tissue engineering," has raised tremendous attention.
[0004] Tissue engineering involves the development of biocompatible materials capable of specifically interacting with biological tissues to produce functional tissue equivalents. Tissue engineering has a basic concept of collecting a desired tissue from an individual, isolating cells from the tissue specimen, proliferating cells, and re-introducing those cells back into the same individual or a different individual. In other aspects, gene therapy capable of attracting or generating the desired cells in vivo is utilized.
[0005] Fibroblast cells have been used for the regeneration of chondrocytes or cartilage type cells. The fibroblasts have been proven to induce their differentiation into chondrocytes in a mechanically stressed, hypoxic environment, for example.
However, there is no current scientific evidence to support the use of additional cell types to this mixture.
Disc Degeneration
However, there is no current scientific evidence to support the use of additional cell types to this mixture.
Disc Degeneration
[0006] More than 65 million Americans suffer from lower back pain annually. By age 50, 85% of the population will show evidence of disc degeneration.
Degeneration of the intervertebral disc, which is often called degenerative disc disease (DDD) or osteoarthritis of the spine, is a common disorder of the lower spine. Disc degeneration can lead to disorders such as lumbar spinal stenosis (narrowing of the spinal canal that houses the spinal cord and nerve roots), spondylolisthesis (forward slippage of the disc and vertebra), and retrolisthesis (backward slippage of the disc and vertebra). DDD is a degenerative condition that can be painful and greatly affect the quality of life.
Degeneration of the intervertebral disc, which is often called degenerative disc disease (DDD) or osteoarthritis of the spine, is a common disorder of the lower spine. Disc degeneration can lead to disorders such as lumbar spinal stenosis (narrowing of the spinal canal that houses the spinal cord and nerve roots), spondylolisthesis (forward slippage of the disc and vertebra), and retrolisthesis (backward slippage of the disc and vertebra). DDD is a degenerative condition that can be painful and greatly affect the quality of life.
[0007] Aging is the most common cause of disc degeneration. As the body ages, the discs in the spine lose important cells that make the disc viable, dehydrate, or dry out, and lose their ability to act as shock absorbers between the vertebra. The bones and ligaments that make up the spine also become less flexible and thicken. Unlike muscles, there is minimal blood supply to the discs, so they lack the ability to heal or repair themselves.
DDD can result in chronic low back pain that sometimes radiates to the hips, or there is an aching pain in the buttocks or thighs while walking, for example.
DDD can result in chronic low back pain that sometimes radiates to the hips, or there is an aching pain in the buttocks or thighs while walking, for example.
[0008] It is not clear why some degenerative discs are painful and some are not.
Some people have nerve endings that penetrate more deeply into the annulus fibrosus, or outer layer of the disc, than others, making the disc more susceptible to becoming a source of pain.
Pain that radiates down the leg, known as sciatica or lumbago, is the result of the nerve root encountering the inner disc material, or the nucleus pulposus, an inflammatory substance that also puts pressure on the nerve. These conditions can cause symptoms such as severe leg pain, difficulty standing and walking, and weakness or numbness in the legs. DDD can lead to a chronic debilitating condition and can have a serious negative impact on a person's quality of life. When DDD is severe, traditional non-operative treatment is often ineffective.
Some people have nerve endings that penetrate more deeply into the annulus fibrosus, or outer layer of the disc, than others, making the disc more susceptible to becoming a source of pain.
Pain that radiates down the leg, known as sciatica or lumbago, is the result of the nerve root encountering the inner disc material, or the nucleus pulposus, an inflammatory substance that also puts pressure on the nerve. These conditions can cause symptoms such as severe leg pain, difficulty standing and walking, and weakness or numbness in the legs. DDD can lead to a chronic debilitating condition and can have a serious negative impact on a person's quality of life. When DDD is severe, traditional non-operative treatment is often ineffective.
[0009] It is challenging to restore full tissue function in damaged or diseased spinal discs. Although there are traditional methods like artificial disc replacements or nucleus substitute, there still exist many shortcomings associated with these therapies. Artificial disc replacements may be prone to dislodgement and transference of mechanical stress to other vertebra above or below the affected area, known as a cascading effect, for example
[0010] The present disclosure concerns efficient and simple methods and compositions to successfully repair and/or regenerate spinal disc, for example.
SUMMARY OF THE INVENTION
[00111 Embodiments of the disclosure concern methods and compositions for repair of a joint in a mammalian individual, such as a human, dog, cat, or horse, for example.
Although the joint may be of any kind, in specific embodiments the joint is a spinal disc, although multiple spinal discs may be treated at the same or different times in a mammalian individual. Methods and compositions of the disclosure utilize one or more nucleus pulposus components, such as notochordal cells, small chondrocyte-like cells, collagen (such as type II
collagen and/or collagen types I, V, VI, IX and XII) fibrils, and/or proteoglycans (such as aggrecan), for example, for repair and/or regeneration of tissue or other matter in a joint.
[0012] The present disclosure concerns a therapeutic delivery (for example, by injection or open application via surgical site) of allogeneic, autologous, or xenogeneic cells (such as nucleus pulposus cells), and/or conditioned medium therefrom, to a joint (including a spinal disc) of a mammal in need thereof. In some embodiments, the nucleus pulposus cells (in addition to, or alternatively to, cells that can differentiate into nucleus pulposus cells) are provided with one or more other therapeutic agents. Although the one or more other therapeutic agents may be of any kind, in specific embodiments the agent(s) is a cell, protein, nucleic acid (including a coding sequence, miRNA, mRNA, DNA, shRNA, siRNA, a combination thereof, and the like), small molecule, or combination thereof. The one or more other therapeutic agents may or may not be a component from the nucleus pulposus.
[0013] In specific embodiments, a therapeutic agent to be provided to the joint (in addition to nucleus pulposus cells or one or more components from nucleus pulposus) is a small molecule, an expressible nucleic acid, a peptide, a protein, or a combination thereof. Although a variety of nucleic acid(s), peptide(s), and/or protein(s) may be provided with the cells, in specific embodiments the nucleic acid(s), peptide(s), or protein(s) comprise Sox9 and/or platelet-rich plasma (PRP) and/or other nucleic acid(s), peptide(s), or protein(s) that aid in the repair and/or regeneration of cartilage. In specific embodiments, the nucleus pulposus cells and/or cells that can differentiate into nucleus pulposus cells are provided in addition to one or more components of the NP (such as notochordal cells and/or Tie2+ cells), including with or without a nutrient matrix or vessel.
[0014] In certain embodiments, the present disclosure relates to methods and compositions for biological repair of cartilage (such as in a joint), for example in the spinal disc or other cartilage, using delivery of at least one cartilage-forming mixture.
This therapy can act as an in vivo workstation for cartilage restoration, in specific embodiments.
In some cases, one or more of the cells and/or other therapeutic agent(s) are provided with an inert device.
Although the inert device may be of any kind, in specific embodiments, the inert device comprises a structure that comprises two generally concentric inflatable membranes. One or more of the cells and/or other therapeutic agent(s) may or may not be provided to an individual with a scaffold.
[0015] The present disclosure encompasses methods for improving the condition of an aged disc in an individual by providing an effective amount of a cell blend from a healthy disc. Also included are methods for improving the condition of an aged disc in an individual by providing an effective amount of a cell blend one might find in a younger and more healthy disc.
Methods of the disclosure include those in which one improves the condition of an aged disc in an individual by providing to the individual with the aged disc an effective amount of a cell blend that one would find in a disc of a person without the onset of the degenerative process.
One embodiment of the disclosure includes a method of improving the condition of an aged disc in an individual by providing to the individual with the aged disc an effective amount of a cell blend from, or that one would be found in, one or more discs of one or more persons without the onset of the degenerative process. A cell blend that would be found in one or more discs of one or more persons without the onset of the degenerative process may include an effective amount of nucleus pulpous cells, chondrocytes, fibroblasts (including at least dermal fibroblasts or fibroblasts from connective tissue in the body, including bone, cartilage and/or muscle), stem cells, and/or adipocytes. The cell blend may also comprise non-cellular components, such as collagen fibrils, proteoglycans, and/or aggrecan, for example.
[0016] As referred to herein, the onset of disc degeneration may include one or more symptoms of pain and in some cases radiating weakness or numbness stemming from a degenerated disc in the spine and/or disc degeneration may include the breakdown of one or more spinal discs that may include the loss of fluid in the disc and/or tiny tears or cracks in the outer layer (annulus or capsule) of the disc (and, in some cases, the nucleus inside the disc is forced out through the tears or cracks in the capsule, which causes the disc to bulge, break open (rupture), or break into fragments).
[0017]
Any disc in the spine may be treated with methods of the disclosure, but in specific cases the discs are in the lower back (lumbar region) and/or the neck (cervical region).
[0018]
In specific cases, the methods may employ a scaffold with one or more compositions. A scaffold used for the regeneration of biological tissue may be comprised of a material that serves as matrix to allow cells to attach to the surface of the material and form a three dimensional tissue. This material may be non-toxic, biocompatible and/or biodegradable, in specific embodiments.
The most widely used biodegradable polymers, satisfying the aforementioned physical requirements, include organic polymers such as polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), poly-c-caprolactone (PCL), polyamino acids, polyanhydrides, polyorthoesters; natural hydrogels such as collagen, hyaluronic acid, alginate, agarose, chitosan; synthetic hydrogels such as poly(ethylene oxide) (PEO), poly(vinyl alcohol) (PVA), poly(acrylic acid) (PAA), poly(propylene fumarate-co-ethylene glycol) [P(PF-co-EG) and copolymers thereof, for example.
[0019]
In certain aspects, cartilage generation may begin at least in part in vitro, using autologous or allogeneic or xenogeneic nucleus pulpous cells (or a mixture thereof), chondrocytes, fibroblasts (including at least dermal fibroblasts or fibroblasts from connective tissue in the body, including bone, cartilage and/or muscle), stem cells, and/or adipocytes, for example. Any cells or mixture of cells can then be delivered to or into the joint(s) or in the vicinity of the joint(s). In embodiments wherein fibroblasts are present in the mixture, the fibroblasts may attract other non-captured fibroblasts into the cartilage regeneration process, in specific embodiments. In particular embodiments, the cells or mixture of types of cells is provided to the individual with one or more other therapeutic agents. A
cellular component of the delivery may occur at the same or a different time as a non-cellular component of the delivery.
[0020]
In certain embodiments, a matrix may be introduced and then seeded either in vitro or in vivo with the gene therapy and/or fibroblasts and/or chondrocytes to provide structure to the cartilage regeneration process.
[0021]
Differentiation of cells into chondrocytes or chondrocyte-like cells may occur in any suitable manner, including a) differentiation of cells in vitro prior to delivery of the cells into the individual; b) differentiation of cells in vitro prior to delivery of the cells into the individual and also in vivo following delivery; and/or c) differentiation in vivo following delivery of the cells. Delivery may comprise implantation of one or more compositions of the cells. In some cases, the cells are provided to an individual with a needle-like instrument with a long tube open at the distal end.
[0022] Embodiments of the disclosure include methods of generating chondrocytes or chondrocyte-like cells for an individual, comprising the step of providing to a degenerated disc of an individual an effective amount of components from the nucleus pulposus (NP) of the same individual or another individual from the same or different species. In specific embodiments, components from the NP comprise notochordal cells, small chondrocyte-like cells, collagen fibrils, proteoglycans, and/or aggrecan. One or more therapeutic agents may also be provided to the degenerated disc of the individual, in some cases, such as one or more therapeutic agents that comprise nucleic acid, peptide, protein, small molecule, or a combination thereof. Alternatively, the one or more therapeutic agents are provided to a cell mixture in vitro prior to delivery of the cell mixture to the individual. In certain embodiments, nucleic acids, peptides, and/or polypeptides that are therapeutic agents themselves are delivered into cells that are to be provided to the individual.
[0023] In specific embodiments, the method comprises the step of providing to the individual one or more compositions comprising an effective amount of one or more of the following: a) fibroblasts; b) notochordal cells; c) Tie2+ cells; d) Tie2 gene product; e) platelet-rich plasma (PRP); f) Sox9 gene product g) transforming growth factor beta-1 (TGFB1); h) connective tissue growth factor (CTGF); i) WNT1-inducible-signaling pathway protein 1 (WISP1), and/or j) WISP2. In at least certain cases, cells of the NP are modified ex vivo prior to providing them to the individual. Cells used in the disclosure, including fibroblasts, notochordal cells, and/or Tie2+ cells, may be modified ex vivo. In some cases, cells are exposed to hypoxia, mechanical strain, or a combination thereof prior to the providing step.
[0024] Certain cells of the disclosure are modified to produce a certain product by the cells, such as the Tie2 gene product and/or the Sox9 gene product. In a specific embodiment, a cell to be delivered to an individual comprises or is modified to express a gene product selected from the group consisting of COL1A1, COL1A2, COL2A1, COL3A1, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6, COL5A1, COL5A2, COL5A3, COL6A1, COL6A2, COL6A3, COL6A4, COL6A5, COL7A1, COL8A1, COL8A2, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1, COL11A2, COL12A1, COL13A1, COL14A1, COL15A1, COL16A1, COL17A1, COL18A1, COL19A1, COL20A1, COL21A1, COL22A1, COL23A1, COL24A1, COL25A1, COL26A1, COL27A1, COL28A1, Gata4, Mef2C, Tbx5, Sox5, Sox6, Sox9, FGFR2, VEGF, MMP14, forkhead, CD10, MMP13, WNT11, BAPX1, IL-1R1, IGFBP5, MMP16, BMP2, ALK1, BMP5, IGF1, MMP13, ADAMTS5, BCL10, MCOLN2, LRRC8C, PTGFR, RLF, MATN1, PDPN, TNFRSF18, ITGA10, THBS3, SCYL1BP1, KCNT2, 244533 at, ARF1, 222348 at, SLC4A5, HSPC159, RHOQ, MATN3, SULT1C2, 236289 at, BCL2L11, F1116008, KLF7, NRP2, SERPINTE2, FN1, B3GNT7, ADAMTS9, ANKRD28, GALNTL2, IRAK2, SETD5, FNDC3B, B3GNT5, CYTL1, IBSP, 229221 at, PET112L, EDNRA, 1563414 at, OSMR, C1QTNF3, ZFYVE16, 225611 at, MAST4, EDIL3, 230204 at, 230895 at, HAPLN1, PDLIM4, cr5q35 SQSTM1, SCUBE3, CMAH, 236685 at, BMP6, ULBP2, LRP11, 50D2, SYNJ2, WTAP, HIG2, KIAA1718, FAM62B, UBE3C, TNFRSF10D, 5LC25A37, ChGn, RB1CC1, C8orf72, EIF2C2, HAS2, TRPS1, WISP1, 235821 at, PTK2, ZCCHC7, RPS6, GLIS3, 5LC28A3, 1555841 at, MGC17337, EDG2, 229242 at, ITGB1, C10orf49, YME1L1, AKR1C2, CHST3, LOXL4, SFXN3, 228910 at, CD44, FOSL1, RELA, MMP12, MMP13, MMP3, KIAA0999, ASAM, L0C399959, ETNK1, SOX5, CHST11, ATF1, SRGAP1, DSPG3, L0C338758, KIAA0701, SLC41A2, RHOF, FZD10, NUPL1, USP12, UFM1, LECT1, GPC6, ERO1L, BDKRB1, SEMA6D, LACTB, ARIH1, CSPG4, AGC1, L0C283824, VASN, WWP2, NOS2A, L0C201181, MSI2, PITPNC1, TGIF, 1552288 at, 1552289 a at, ZNF146, RELB, MIA, ZNF160, SNX5, BMP2, RNF24, HSUP1, MATN4, BIC, RUNX1, LIF, RP4-756G23.1, RPS6KA3, TNMD, RP6-213H19.1, and a combination thereof.
[00251 Cells of the disclosure may be autologous, allogeneic, or xenogeneic in relation to the individual.
[0026] In some embodiments, a method further comprises detection of the degenerated disc, such as by measuring the level of notochord cells in the NP
of a disc in the individual suspected of being degenerated. The degenerated disc may be detected structurally or non-structurally (such as by monitoring the level of cells, including notochordal cells, in the disc). Non-structural detection may comprise biochemical or molecular means.
Detection of the state of the degenerated disc, or the level of notochord cells in the NP of a disc, may or may not occur prior to delivery to the disc of one or more compositions of this disclosure.
[00271 In some embodiments, there is a method of repairing and/or regenerating cartilage in a spinal disc of an individual in need thereof, comprising the steps of: a) providing fibroblasts, stem cells, adipocytes, or a combination thereof to the disc of the individual; b) providing one or more components from the nucleus pulposus (NP) to the disc of the individual;
and c) providing one or more of the following to the disc of the individual:
1) Tie2+ cells; 2) Tie2 gene product; 3) platelet-rich plasma (PRP); 4) PRP+ cells; 5) Sox9 gene product; 6) Sox9+
gene product; 7) TGFB1 gene product; 8) TGFB1+ cells; 9) CTGF gene product;
10) CTGF+
cells; 11) WISP1 gene product; 12) WISP1+ cells; 13) WISP2 gene product;
and/or 14) WISP2+
cells. In specific embodiments, one or more components of the NP comprise notochordal cells, small chondrocyte-like cells, collagen fibrils, and/or aggrecan. In certain cases, step a) occurs prior to steps b) and/or c).
[0028] In another embodiment, there is a method of repairing and/or regenerating cartilage in a spinal disc of an individual in need thereof, comprising the steps of: combining one or more of the compositions listed in a), b) and/or c) with another one or more of the compositions listed in a), b), and/or c) to produce a mixture: a) fibroblasts, stem cells, adipocytes, or a combination thereof; b) one or more components from the nucleus pulposus (NP); c) one or more of the following: 1) Tie2+ cells; 2) Tie2 gene product;
3) platelet-rich plasma (PRP); 4) PRP+ cells; 5) Sox9 gene product; 6) Sox9+ cells; 7) TGFB1 gene product; 8) TGFB1+ cells; 9) CTGF gene product; 10) CTGF+ cells; 11) WISP1 gene product;
12) WISP1+
cells, 13) WISP2 gene product; and/or 14) WISP2+ cells; and providing the mixture to the individual. In specific aspects, the mixture is generated in vitro or is generated in vivo. In specific cases, the mixture is delivered to the individual by injection or by insertion via open incision.
[0029] In particular embodiments, methods of the disclosure include delivering a therapeutically effective amount of notochordal cells and/or notochordal cell conditioned medium to an individual in need thereof, including an individual with degenerative disc(s), for example. In specific embodiments, in addition to notochordal cell conditioned medium or one or more components therefrom, an individual is provided with an effective amount of notochordal cells, small chondrocyte-like cells, collagen fibrils, proteoglycans, and/or aggrecan, for example.
The notochordal cell conditioned medium regenerates the degenerative disc or regenerates a portion thereof or generates chondrocytes or chondrocyte-like cells in the individual. Providing the notochordal cell conditioned medium to the individual may treat degenerative disc, reverse degenerative disc, prevent degenerative disc, or prevent further deterioration of degenerative disc. In specific embodiments, the notochordal cell conditioned medium is serum free. In specific embodiments, one or more components from notochordal cells and/or notochordal cell conditioned medium comprises transforming growth factor beta-1 (TGFB1), connective tissue growth factor (CTGF, also called CCN2), WNT1-inducible-signaling pathway protein 1 (WISP1), and/or WISP2. In some cases, in addition to or instead of delivering notochordal cells and/or notochordal cell conditioned medium to the individual, one may deliver TGFB1, CTGF, WISP1, and/or WISP2 to the individual, either in protein form or in nucleic acid form. Upon delivery of notochordal cells and/or notochordal cell conditioned medium and/or TGFB1, CTGF, WISP1, and/or WISP2, there is retention of notochordal cells and/or stem cells in the nucleus pulposus, as compared to loss of notochordal cells and/or stem cells in the absence of such a delivery.
[0030] An individual may receive multiple administrations of the therapeutic composition(s), and the separate administrations may be delivered within any span of time, such as within days, weeks, months, and/or years of another. An individual may receive administrations of multiple therapeutic composition(s) of the disclosure via different routes. In some cases, an individual yet to have one or more symptoms of a degenerated disc are provided one or more therapeutic composition(s) of the disclosure. In certain cases, an individual is provided an effective amount of one or more therapeutic composition(s) of the disclosure beginning at a certain age, such as at 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 years, and so forth. In particular aspects, an individual prone to having a degenerated disc is provided an effective amount of one or more therapeutic composition(s) of the disclosure regardless of whether or not one or more symptoms of a degenerated disc have been detected for the individual. An individual prone to have a degenerated disc includes one that engages in repetitive activities, one having an injury to the spine, one that participates in athletics (including high-contact athletics), and/or one having a job that requires heavy lifting, for example.
[0031] In some cases, an effective amount of one or more components from the nucleus pulposus (NP) are provided to an individual in need of receiving the one or more components from the NP; in specific cases the one or more components from the NP include notochordal cells, notochordal cell conditioned media, small chondrocyte-like cells, collagen fibrils, proteoglycans, and/or aggrecan, for example. The individual may be provided a therapeutic agent also. In particular embodiments, the individual is provided one or more components from the NP for the purpose of specifically providing the one or more components from the NP to the individual. An individual may be determined to need the one or more components from the NP prior to specifically providing the one or more components from the NP to the individual. In some cases, the individual is specifically provided one or more components from the NP but is specifically not provided one or more other components from the NP. In specific cases, a substantially entire content of NP is or is not provided to an individual.
In particular embodiments, an individual is provided an effective amount of a composition that comprises, consists essentially of, or consists of one or more components from the NP, such as one or more of notochordal cells, notochordal cell conditioned media, small chondrocyte-like cells, collagen fibrils, proteoglycans, and/or aggrecan, for example.
[0032] The foregoing has outlined rather broadly the features and technical advantages of the present invention in order that the detailed description of the invention that follows may be better understood. Additional features and advantages of the invention will be described hereinafter which form the subject of the claims of the invention.
It should be appreciated by those skilled in the art that the conception and specific embodiment disclosed may be readily utilized as a basis for modifying or designing other structures for carrying out the same purposes of the present invention. It should also be realized by those skilled in the art that such equivalent constructions do not depart from the spirit and scope of the invention as set forth in the appended claims. The novel features which are believed to be characteristic of the invention, both as to its organization and method of operation, together with further objects and advantages will be better understood from the following description when considered in connection with the accompanying figures. It is to be expressly understood, however, that each of the figures is provided for the purpose of illustration and description only and is not intended as a definition of the limits of the present invention. The present application refers to a number of references and documents all of which are incorporated herein in their entirety.
DETAILED DESCRIPTION
[0033] As used herein the specification, "a" or "an" may mean one or more. As used herein in the claim(s), when used in conjunction with the word "comprising", the words "a"
or "an" may mean one or more than one. As used herein "another" may mean at least a second or more. In specific embodiments, aspects of the invention may "consist essentially of' or "consist of' one or more sequences of the invention, for example. Some embodiments of the invention may consist of or consist essentially of one or more elements, method steps, and/or methods of the invention. It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein.
[0034] U.S. Patent No. 7850983, U.S. Patent Publication US
2014/0314726; U.S.
Patent Publication US 2014/0044682; U.S. Patent Publication US 2014/0377231;
and WO/2015/035395 are incorporated by reference herein in their entirety.
I. [0035] Definitions [0036] The term "chondrocyte-like cells" as used herein refers to cells that are not primary chondrocytes but are derived from stem cells (such as mesenchymal stem cells) or cells from other lineages (such as fibroblasts). These chondrocyte-like cells have a phenotype of chondrocytes (cells of cartilage). This means that not only do they have a shape of chondrocytes (polygonal and/or rhomboidal cells, for example), but also they are able to aggregate and produce cartilage matrix components, such as sulfated proteoglycan and type II
collagen, for example. Thus, exemplary markers of chondrocyte-like cells include one or more of aggrecan, which is a chondroitin sulfate and keratan sulfate proteoglycan, type II
collagen, Sox-9 protein, cartilage link protein, and perlecan, which is a heparan sulfate proteoglycan, for example.
[0037] The term "hypoxia" as used herein refers to a deficiency in oxygen. In specific aspects, it refers to oxygen tension that is less than about 20%, 15%, 10%, 5%, and so forth.
[0038] The term "joint" as used herein refers to a region in the body wherein two bones of a skeleton join.
[0039] In certain embodiments, the term "seeding" as used herein refers to implanting cells in a scaffold, and the scaffold may be present in a disc or may be present in vitro. The cells will attach to the scaffold and then grow and differentiate in the scaffold. In specific embodiments, the term "seeding" refers to seeding the cells into the nucleus pulpous via direct injection without a scaffold. This differentiation can occur both in vitro and in vivo.
II. [0040] General Embodiments [0041] As a rapidly expanding field, tissue engineering provides alternative solutions for articular cartilage repair and regeneration through developing biomimetic tissue substitutes, in at least some cases. In some embodiments of the disclosure, there are methods and compositions related to repair and/or regeneration of tissue, including cartilage. As used herein, the term "repair" denotes the restoration of normal function of cartilage regardless of the composition of new tissue that fills the defect sites. As used herein, "regeneration" is defined as
SUMMARY OF THE INVENTION
[00111 Embodiments of the disclosure concern methods and compositions for repair of a joint in a mammalian individual, such as a human, dog, cat, or horse, for example.
Although the joint may be of any kind, in specific embodiments the joint is a spinal disc, although multiple spinal discs may be treated at the same or different times in a mammalian individual. Methods and compositions of the disclosure utilize one or more nucleus pulposus components, such as notochordal cells, small chondrocyte-like cells, collagen (such as type II
collagen and/or collagen types I, V, VI, IX and XII) fibrils, and/or proteoglycans (such as aggrecan), for example, for repair and/or regeneration of tissue or other matter in a joint.
[0012] The present disclosure concerns a therapeutic delivery (for example, by injection or open application via surgical site) of allogeneic, autologous, or xenogeneic cells (such as nucleus pulposus cells), and/or conditioned medium therefrom, to a joint (including a spinal disc) of a mammal in need thereof. In some embodiments, the nucleus pulposus cells (in addition to, or alternatively to, cells that can differentiate into nucleus pulposus cells) are provided with one or more other therapeutic agents. Although the one or more other therapeutic agents may be of any kind, in specific embodiments the agent(s) is a cell, protein, nucleic acid (including a coding sequence, miRNA, mRNA, DNA, shRNA, siRNA, a combination thereof, and the like), small molecule, or combination thereof. The one or more other therapeutic agents may or may not be a component from the nucleus pulposus.
[0013] In specific embodiments, a therapeutic agent to be provided to the joint (in addition to nucleus pulposus cells or one or more components from nucleus pulposus) is a small molecule, an expressible nucleic acid, a peptide, a protein, or a combination thereof. Although a variety of nucleic acid(s), peptide(s), and/or protein(s) may be provided with the cells, in specific embodiments the nucleic acid(s), peptide(s), or protein(s) comprise Sox9 and/or platelet-rich plasma (PRP) and/or other nucleic acid(s), peptide(s), or protein(s) that aid in the repair and/or regeneration of cartilage. In specific embodiments, the nucleus pulposus cells and/or cells that can differentiate into nucleus pulposus cells are provided in addition to one or more components of the NP (such as notochordal cells and/or Tie2+ cells), including with or without a nutrient matrix or vessel.
[0014] In certain embodiments, the present disclosure relates to methods and compositions for biological repair of cartilage (such as in a joint), for example in the spinal disc or other cartilage, using delivery of at least one cartilage-forming mixture.
This therapy can act as an in vivo workstation for cartilage restoration, in specific embodiments.
In some cases, one or more of the cells and/or other therapeutic agent(s) are provided with an inert device.
Although the inert device may be of any kind, in specific embodiments, the inert device comprises a structure that comprises two generally concentric inflatable membranes. One or more of the cells and/or other therapeutic agent(s) may or may not be provided to an individual with a scaffold.
[0015] The present disclosure encompasses methods for improving the condition of an aged disc in an individual by providing an effective amount of a cell blend from a healthy disc. Also included are methods for improving the condition of an aged disc in an individual by providing an effective amount of a cell blend one might find in a younger and more healthy disc.
Methods of the disclosure include those in which one improves the condition of an aged disc in an individual by providing to the individual with the aged disc an effective amount of a cell blend that one would find in a disc of a person without the onset of the degenerative process.
One embodiment of the disclosure includes a method of improving the condition of an aged disc in an individual by providing to the individual with the aged disc an effective amount of a cell blend from, or that one would be found in, one or more discs of one or more persons without the onset of the degenerative process. A cell blend that would be found in one or more discs of one or more persons without the onset of the degenerative process may include an effective amount of nucleus pulpous cells, chondrocytes, fibroblasts (including at least dermal fibroblasts or fibroblasts from connective tissue in the body, including bone, cartilage and/or muscle), stem cells, and/or adipocytes. The cell blend may also comprise non-cellular components, such as collagen fibrils, proteoglycans, and/or aggrecan, for example.
[0016] As referred to herein, the onset of disc degeneration may include one or more symptoms of pain and in some cases radiating weakness or numbness stemming from a degenerated disc in the spine and/or disc degeneration may include the breakdown of one or more spinal discs that may include the loss of fluid in the disc and/or tiny tears or cracks in the outer layer (annulus or capsule) of the disc (and, in some cases, the nucleus inside the disc is forced out through the tears or cracks in the capsule, which causes the disc to bulge, break open (rupture), or break into fragments).
[0017]
Any disc in the spine may be treated with methods of the disclosure, but in specific cases the discs are in the lower back (lumbar region) and/or the neck (cervical region).
[0018]
In specific cases, the methods may employ a scaffold with one or more compositions. A scaffold used for the regeneration of biological tissue may be comprised of a material that serves as matrix to allow cells to attach to the surface of the material and form a three dimensional tissue. This material may be non-toxic, biocompatible and/or biodegradable, in specific embodiments.
The most widely used biodegradable polymers, satisfying the aforementioned physical requirements, include organic polymers such as polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), poly-c-caprolactone (PCL), polyamino acids, polyanhydrides, polyorthoesters; natural hydrogels such as collagen, hyaluronic acid, alginate, agarose, chitosan; synthetic hydrogels such as poly(ethylene oxide) (PEO), poly(vinyl alcohol) (PVA), poly(acrylic acid) (PAA), poly(propylene fumarate-co-ethylene glycol) [P(PF-co-EG) and copolymers thereof, for example.
[0019]
In certain aspects, cartilage generation may begin at least in part in vitro, using autologous or allogeneic or xenogeneic nucleus pulpous cells (or a mixture thereof), chondrocytes, fibroblasts (including at least dermal fibroblasts or fibroblasts from connective tissue in the body, including bone, cartilage and/or muscle), stem cells, and/or adipocytes, for example. Any cells or mixture of cells can then be delivered to or into the joint(s) or in the vicinity of the joint(s). In embodiments wherein fibroblasts are present in the mixture, the fibroblasts may attract other non-captured fibroblasts into the cartilage regeneration process, in specific embodiments. In particular embodiments, the cells or mixture of types of cells is provided to the individual with one or more other therapeutic agents. A
cellular component of the delivery may occur at the same or a different time as a non-cellular component of the delivery.
[0020]
In certain embodiments, a matrix may be introduced and then seeded either in vitro or in vivo with the gene therapy and/or fibroblasts and/or chondrocytes to provide structure to the cartilage regeneration process.
[0021]
Differentiation of cells into chondrocytes or chondrocyte-like cells may occur in any suitable manner, including a) differentiation of cells in vitro prior to delivery of the cells into the individual; b) differentiation of cells in vitro prior to delivery of the cells into the individual and also in vivo following delivery; and/or c) differentiation in vivo following delivery of the cells. Delivery may comprise implantation of one or more compositions of the cells. In some cases, the cells are provided to an individual with a needle-like instrument with a long tube open at the distal end.
[0022] Embodiments of the disclosure include methods of generating chondrocytes or chondrocyte-like cells for an individual, comprising the step of providing to a degenerated disc of an individual an effective amount of components from the nucleus pulposus (NP) of the same individual or another individual from the same or different species. In specific embodiments, components from the NP comprise notochordal cells, small chondrocyte-like cells, collagen fibrils, proteoglycans, and/or aggrecan. One or more therapeutic agents may also be provided to the degenerated disc of the individual, in some cases, such as one or more therapeutic agents that comprise nucleic acid, peptide, protein, small molecule, or a combination thereof. Alternatively, the one or more therapeutic agents are provided to a cell mixture in vitro prior to delivery of the cell mixture to the individual. In certain embodiments, nucleic acids, peptides, and/or polypeptides that are therapeutic agents themselves are delivered into cells that are to be provided to the individual.
[0023] In specific embodiments, the method comprises the step of providing to the individual one or more compositions comprising an effective amount of one or more of the following: a) fibroblasts; b) notochordal cells; c) Tie2+ cells; d) Tie2 gene product; e) platelet-rich plasma (PRP); f) Sox9 gene product g) transforming growth factor beta-1 (TGFB1); h) connective tissue growth factor (CTGF); i) WNT1-inducible-signaling pathway protein 1 (WISP1), and/or j) WISP2. In at least certain cases, cells of the NP are modified ex vivo prior to providing them to the individual. Cells used in the disclosure, including fibroblasts, notochordal cells, and/or Tie2+ cells, may be modified ex vivo. In some cases, cells are exposed to hypoxia, mechanical strain, or a combination thereof prior to the providing step.
[0024] Certain cells of the disclosure are modified to produce a certain product by the cells, such as the Tie2 gene product and/or the Sox9 gene product. In a specific embodiment, a cell to be delivered to an individual comprises or is modified to express a gene product selected from the group consisting of COL1A1, COL1A2, COL2A1, COL3A1, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6, COL5A1, COL5A2, COL5A3, COL6A1, COL6A2, COL6A3, COL6A4, COL6A5, COL7A1, COL8A1, COL8A2, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1, COL11A2, COL12A1, COL13A1, COL14A1, COL15A1, COL16A1, COL17A1, COL18A1, COL19A1, COL20A1, COL21A1, COL22A1, COL23A1, COL24A1, COL25A1, COL26A1, COL27A1, COL28A1, Gata4, Mef2C, Tbx5, Sox5, Sox6, Sox9, FGFR2, VEGF, MMP14, forkhead, CD10, MMP13, WNT11, BAPX1, IL-1R1, IGFBP5, MMP16, BMP2, ALK1, BMP5, IGF1, MMP13, ADAMTS5, BCL10, MCOLN2, LRRC8C, PTGFR, RLF, MATN1, PDPN, TNFRSF18, ITGA10, THBS3, SCYL1BP1, KCNT2, 244533 at, ARF1, 222348 at, SLC4A5, HSPC159, RHOQ, MATN3, SULT1C2, 236289 at, BCL2L11, F1116008, KLF7, NRP2, SERPINTE2, FN1, B3GNT7, ADAMTS9, ANKRD28, GALNTL2, IRAK2, SETD5, FNDC3B, B3GNT5, CYTL1, IBSP, 229221 at, PET112L, EDNRA, 1563414 at, OSMR, C1QTNF3, ZFYVE16, 225611 at, MAST4, EDIL3, 230204 at, 230895 at, HAPLN1, PDLIM4, cr5q35 SQSTM1, SCUBE3, CMAH, 236685 at, BMP6, ULBP2, LRP11, 50D2, SYNJ2, WTAP, HIG2, KIAA1718, FAM62B, UBE3C, TNFRSF10D, 5LC25A37, ChGn, RB1CC1, C8orf72, EIF2C2, HAS2, TRPS1, WISP1, 235821 at, PTK2, ZCCHC7, RPS6, GLIS3, 5LC28A3, 1555841 at, MGC17337, EDG2, 229242 at, ITGB1, C10orf49, YME1L1, AKR1C2, CHST3, LOXL4, SFXN3, 228910 at, CD44, FOSL1, RELA, MMP12, MMP13, MMP3, KIAA0999, ASAM, L0C399959, ETNK1, SOX5, CHST11, ATF1, SRGAP1, DSPG3, L0C338758, KIAA0701, SLC41A2, RHOF, FZD10, NUPL1, USP12, UFM1, LECT1, GPC6, ERO1L, BDKRB1, SEMA6D, LACTB, ARIH1, CSPG4, AGC1, L0C283824, VASN, WWP2, NOS2A, L0C201181, MSI2, PITPNC1, TGIF, 1552288 at, 1552289 a at, ZNF146, RELB, MIA, ZNF160, SNX5, BMP2, RNF24, HSUP1, MATN4, BIC, RUNX1, LIF, RP4-756G23.1, RPS6KA3, TNMD, RP6-213H19.1, and a combination thereof.
[00251 Cells of the disclosure may be autologous, allogeneic, or xenogeneic in relation to the individual.
[0026] In some embodiments, a method further comprises detection of the degenerated disc, such as by measuring the level of notochord cells in the NP
of a disc in the individual suspected of being degenerated. The degenerated disc may be detected structurally or non-structurally (such as by monitoring the level of cells, including notochordal cells, in the disc). Non-structural detection may comprise biochemical or molecular means.
Detection of the state of the degenerated disc, or the level of notochord cells in the NP of a disc, may or may not occur prior to delivery to the disc of one or more compositions of this disclosure.
[00271 In some embodiments, there is a method of repairing and/or regenerating cartilage in a spinal disc of an individual in need thereof, comprising the steps of: a) providing fibroblasts, stem cells, adipocytes, or a combination thereof to the disc of the individual; b) providing one or more components from the nucleus pulposus (NP) to the disc of the individual;
and c) providing one or more of the following to the disc of the individual:
1) Tie2+ cells; 2) Tie2 gene product; 3) platelet-rich plasma (PRP); 4) PRP+ cells; 5) Sox9 gene product; 6) Sox9+
gene product; 7) TGFB1 gene product; 8) TGFB1+ cells; 9) CTGF gene product;
10) CTGF+
cells; 11) WISP1 gene product; 12) WISP1+ cells; 13) WISP2 gene product;
and/or 14) WISP2+
cells. In specific embodiments, one or more components of the NP comprise notochordal cells, small chondrocyte-like cells, collagen fibrils, and/or aggrecan. In certain cases, step a) occurs prior to steps b) and/or c).
[0028] In another embodiment, there is a method of repairing and/or regenerating cartilage in a spinal disc of an individual in need thereof, comprising the steps of: combining one or more of the compositions listed in a), b) and/or c) with another one or more of the compositions listed in a), b), and/or c) to produce a mixture: a) fibroblasts, stem cells, adipocytes, or a combination thereof; b) one or more components from the nucleus pulposus (NP); c) one or more of the following: 1) Tie2+ cells; 2) Tie2 gene product;
3) platelet-rich plasma (PRP); 4) PRP+ cells; 5) Sox9 gene product; 6) Sox9+ cells; 7) TGFB1 gene product; 8) TGFB1+ cells; 9) CTGF gene product; 10) CTGF+ cells; 11) WISP1 gene product;
12) WISP1+
cells, 13) WISP2 gene product; and/or 14) WISP2+ cells; and providing the mixture to the individual. In specific aspects, the mixture is generated in vitro or is generated in vivo. In specific cases, the mixture is delivered to the individual by injection or by insertion via open incision.
[0029] In particular embodiments, methods of the disclosure include delivering a therapeutically effective amount of notochordal cells and/or notochordal cell conditioned medium to an individual in need thereof, including an individual with degenerative disc(s), for example. In specific embodiments, in addition to notochordal cell conditioned medium or one or more components therefrom, an individual is provided with an effective amount of notochordal cells, small chondrocyte-like cells, collagen fibrils, proteoglycans, and/or aggrecan, for example.
The notochordal cell conditioned medium regenerates the degenerative disc or regenerates a portion thereof or generates chondrocytes or chondrocyte-like cells in the individual. Providing the notochordal cell conditioned medium to the individual may treat degenerative disc, reverse degenerative disc, prevent degenerative disc, or prevent further deterioration of degenerative disc. In specific embodiments, the notochordal cell conditioned medium is serum free. In specific embodiments, one or more components from notochordal cells and/or notochordal cell conditioned medium comprises transforming growth factor beta-1 (TGFB1), connective tissue growth factor (CTGF, also called CCN2), WNT1-inducible-signaling pathway protein 1 (WISP1), and/or WISP2. In some cases, in addition to or instead of delivering notochordal cells and/or notochordal cell conditioned medium to the individual, one may deliver TGFB1, CTGF, WISP1, and/or WISP2 to the individual, either in protein form or in nucleic acid form. Upon delivery of notochordal cells and/or notochordal cell conditioned medium and/or TGFB1, CTGF, WISP1, and/or WISP2, there is retention of notochordal cells and/or stem cells in the nucleus pulposus, as compared to loss of notochordal cells and/or stem cells in the absence of such a delivery.
[0030] An individual may receive multiple administrations of the therapeutic composition(s), and the separate administrations may be delivered within any span of time, such as within days, weeks, months, and/or years of another. An individual may receive administrations of multiple therapeutic composition(s) of the disclosure via different routes. In some cases, an individual yet to have one or more symptoms of a degenerated disc are provided one or more therapeutic composition(s) of the disclosure. In certain cases, an individual is provided an effective amount of one or more therapeutic composition(s) of the disclosure beginning at a certain age, such as at 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 years, and so forth. In particular aspects, an individual prone to having a degenerated disc is provided an effective amount of one or more therapeutic composition(s) of the disclosure regardless of whether or not one or more symptoms of a degenerated disc have been detected for the individual. An individual prone to have a degenerated disc includes one that engages in repetitive activities, one having an injury to the spine, one that participates in athletics (including high-contact athletics), and/or one having a job that requires heavy lifting, for example.
[0031] In some cases, an effective amount of one or more components from the nucleus pulposus (NP) are provided to an individual in need of receiving the one or more components from the NP; in specific cases the one or more components from the NP include notochordal cells, notochordal cell conditioned media, small chondrocyte-like cells, collagen fibrils, proteoglycans, and/or aggrecan, for example. The individual may be provided a therapeutic agent also. In particular embodiments, the individual is provided one or more components from the NP for the purpose of specifically providing the one or more components from the NP to the individual. An individual may be determined to need the one or more components from the NP prior to specifically providing the one or more components from the NP to the individual. In some cases, the individual is specifically provided one or more components from the NP but is specifically not provided one or more other components from the NP. In specific cases, a substantially entire content of NP is or is not provided to an individual.
In particular embodiments, an individual is provided an effective amount of a composition that comprises, consists essentially of, or consists of one or more components from the NP, such as one or more of notochordal cells, notochordal cell conditioned media, small chondrocyte-like cells, collagen fibrils, proteoglycans, and/or aggrecan, for example.
[0032] The foregoing has outlined rather broadly the features and technical advantages of the present invention in order that the detailed description of the invention that follows may be better understood. Additional features and advantages of the invention will be described hereinafter which form the subject of the claims of the invention.
It should be appreciated by those skilled in the art that the conception and specific embodiment disclosed may be readily utilized as a basis for modifying or designing other structures for carrying out the same purposes of the present invention. It should also be realized by those skilled in the art that such equivalent constructions do not depart from the spirit and scope of the invention as set forth in the appended claims. The novel features which are believed to be characteristic of the invention, both as to its organization and method of operation, together with further objects and advantages will be better understood from the following description when considered in connection with the accompanying figures. It is to be expressly understood, however, that each of the figures is provided for the purpose of illustration and description only and is not intended as a definition of the limits of the present invention. The present application refers to a number of references and documents all of which are incorporated herein in their entirety.
DETAILED DESCRIPTION
[0033] As used herein the specification, "a" or "an" may mean one or more. As used herein in the claim(s), when used in conjunction with the word "comprising", the words "a"
or "an" may mean one or more than one. As used herein "another" may mean at least a second or more. In specific embodiments, aspects of the invention may "consist essentially of' or "consist of' one or more sequences of the invention, for example. Some embodiments of the invention may consist of or consist essentially of one or more elements, method steps, and/or methods of the invention. It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein.
[0034] U.S. Patent No. 7850983, U.S. Patent Publication US
2014/0314726; U.S.
Patent Publication US 2014/0044682; U.S. Patent Publication US 2014/0377231;
and WO/2015/035395 are incorporated by reference herein in their entirety.
I. [0035] Definitions [0036] The term "chondrocyte-like cells" as used herein refers to cells that are not primary chondrocytes but are derived from stem cells (such as mesenchymal stem cells) or cells from other lineages (such as fibroblasts). These chondrocyte-like cells have a phenotype of chondrocytes (cells of cartilage). This means that not only do they have a shape of chondrocytes (polygonal and/or rhomboidal cells, for example), but also they are able to aggregate and produce cartilage matrix components, such as sulfated proteoglycan and type II
collagen, for example. Thus, exemplary markers of chondrocyte-like cells include one or more of aggrecan, which is a chondroitin sulfate and keratan sulfate proteoglycan, type II
collagen, Sox-9 protein, cartilage link protein, and perlecan, which is a heparan sulfate proteoglycan, for example.
[0037] The term "hypoxia" as used herein refers to a deficiency in oxygen. In specific aspects, it refers to oxygen tension that is less than about 20%, 15%, 10%, 5%, and so forth.
[0038] The term "joint" as used herein refers to a region in the body wherein two bones of a skeleton join.
[0039] In certain embodiments, the term "seeding" as used herein refers to implanting cells in a scaffold, and the scaffold may be present in a disc or may be present in vitro. The cells will attach to the scaffold and then grow and differentiate in the scaffold. In specific embodiments, the term "seeding" refers to seeding the cells into the nucleus pulpous via direct injection without a scaffold. This differentiation can occur both in vitro and in vivo.
II. [0040] General Embodiments [0041] As a rapidly expanding field, tissue engineering provides alternative solutions for articular cartilage repair and regeneration through developing biomimetic tissue substitutes, in at least some cases. In some embodiments of the disclosure, there are methods and compositions related to repair and/or regeneration of tissue, including cartilage. As used herein, the term "repair" denotes the restoration of normal function of cartilage regardless of the composition of new tissue that fills the defect sites. As used herein, "regeneration" is defined as
11 a process that not only restores the normal functions of injured or diseased articular cartilage, but also results in the formation of new tissue that is indistinguishable from or very similar to the native cartilage.
[0042] In particular embodiments, nucleus pulposus cells and/or conditioned medium generated therefrom are provided to an individual in need thereof, such as an individual that has degenerative disc disorder, has a degenerative disc, and so forth, and it may treat or prevent herniated disc, bulging disc, slipped disc, ruptured disc, and so forth. The cells from the nucleus pulposus and/or conditioned medium generated therefrom may be obtained from the individual being treated, such as from a healthy disc from the same individual; they may be obtained from another individual of the same species; or they may be obtained from an individual of another species, for example. Methods of isolating nucleus pulposus cells are known in the art (for example, Gruber et al., 2006; Feng et al., 2013; Tang et al., 2014). The nucleus pulposus cells may be obtained commercially. Methods of generating conditioned medium from cells are known in the art.
[0043] The cells from the nucleus pulposus (and/or any other cells to be delivered to an individual), may be exposed to one or more compositions prior to delivery to an individual in need thereof. For example, the cells may be modified to express one or more compositions that are conducive to cellular health and/or proliferation and/or the cells may be modified to express one or more compositions for cartilage repair and/or regeneration. In specific embodiments, the cells are manipulated to harbor a vector (viral (adenoviral, adeno-associated, lentiviral, retroviral, and so forth) or non-viral (plasmid)) that expresses a particular nucleic acid for therapeutic purposes (wherein the nucleic acid itself is therapeutic or wherein the nucleic acid expresses a therapeutic gene product). In other embodiments, cells or other vectors (such as liposomes) are manipulated to provide a particular protein or functionally active peptide fragment thereof. Proteins may be delivered as fusion proteins, for example a protein of interest may be fused with another protein or protein fragment that facilitates cartilage repair and/or regeneration or the protein of interest may be fused with another protein or protein fragment, such as a marker or label. Examples of proteins that may be provided to the individual, or nucleic acids that encode part or all of them, are as follows: COL1A1, COL1A2, COL2A1, COL3A1, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6, COL5A1, COL5A2, COL5A3, COL6A1, COL6A2, COL6A3, COL6A4, COL6A5, COL7A1, COL8A1, COL8A2, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1, COL11A2, COL12A1, COL13A1,
[0042] In particular embodiments, nucleus pulposus cells and/or conditioned medium generated therefrom are provided to an individual in need thereof, such as an individual that has degenerative disc disorder, has a degenerative disc, and so forth, and it may treat or prevent herniated disc, bulging disc, slipped disc, ruptured disc, and so forth. The cells from the nucleus pulposus and/or conditioned medium generated therefrom may be obtained from the individual being treated, such as from a healthy disc from the same individual; they may be obtained from another individual of the same species; or they may be obtained from an individual of another species, for example. Methods of isolating nucleus pulposus cells are known in the art (for example, Gruber et al., 2006; Feng et al., 2013; Tang et al., 2014). The nucleus pulposus cells may be obtained commercially. Methods of generating conditioned medium from cells are known in the art.
[0043] The cells from the nucleus pulposus (and/or any other cells to be delivered to an individual), may be exposed to one or more compositions prior to delivery to an individual in need thereof. For example, the cells may be modified to express one or more compositions that are conducive to cellular health and/or proliferation and/or the cells may be modified to express one or more compositions for cartilage repair and/or regeneration. In specific embodiments, the cells are manipulated to harbor a vector (viral (adenoviral, adeno-associated, lentiviral, retroviral, and so forth) or non-viral (plasmid)) that expresses a particular nucleic acid for therapeutic purposes (wherein the nucleic acid itself is therapeutic or wherein the nucleic acid expresses a therapeutic gene product). In other embodiments, cells or other vectors (such as liposomes) are manipulated to provide a particular protein or functionally active peptide fragment thereof. Proteins may be delivered as fusion proteins, for example a protein of interest may be fused with another protein or protein fragment that facilitates cartilage repair and/or regeneration or the protein of interest may be fused with another protein or protein fragment, such as a marker or label. Examples of proteins that may be provided to the individual, or nucleic acids that encode part or all of them, are as follows: COL1A1, COL1A2, COL2A1, COL3A1, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6, COL5A1, COL5A2, COL5A3, COL6A1, COL6A2, COL6A3, COL6A4, COL6A5, COL7A1, COL8A1, COL8A2, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1, COL11A2, COL12A1, COL13A1,
12 COL14A1, COL15A1, COL16A1, COL17A1, COL18A1, COL19A1, COL20A1, COL21A1, COL22A1, COL23A1, COL24A1, COL25A1, COL26A1, COL27A1, COL28A1, Gata4, Mef2C, Tbx5, Sox5, Sox6, Sox9, FGFR2, VEGF, MMP14, forkhead, CD10, MMP13, WNT11, BAPX1, IL-1R1, IGFBP5, MMP16, BMP2, ALK1, BMP5, IGF1, MMP13, ADAMTS5, BCL10, MCOLN2, LRRC8C, PTGFR, RLF, MATN1, PDPN, TNFRSF18, ITGA10, THBS3, SCYL1BP1, KCNT2, 244533 at, ARF1, 222348 at, SLC4A5, HSPC159, RHOQ, MATN3, SULT1C2, 236289 at, BCL2L11, F1116008, KLF7, NRP2, SERPINTE2, FN1, B3GNT7, ADAMTS9, ANKRD28, GALNTL2, IRAK2, SETD5, FNDC3B, B3GNT5, CYTL1, IBSP, 229221 at, PET112L, EDNRA, 1563414 at, OSMR, C1QTNF3, ZFYVE16, 225611 at, MAST4, EDIL3, 230204 at, 230895 at, HAPLN1, PDLIM4, cr5q35 SQSTM1, SCUBE3, CMAH, 236685 at, BMP6, ULBP2, LRP11, 50D2, SYNJ2, WTAP, HIG2, KIAA1718, FAM62B, UBE3C, TNFRSF10D, 5LC25A37, ChGn, RB1CC1, C8orf72, EIF2C2, HAS2, TRPS1, WISP1, 235821 at, PTK2, ZCCHC7, RPS6, GLIS3, 5LC28A3, 1555841 at, MGC17337, EDG2, 229242 at, ITGB1, C10orf49, YME1L1, AKR1C2, CHST3, LOXL4, SFXN3, 228910 at, CD44, FOSL1, RELA, MMP12, MMP13, MMP3, KIAA0999, ASAM, L0C399959, ETNK1, SOX5, CHST11, ATF1, SRGAP1, DSPG3, L0C338758, KIAA0701, SLC41A2, RHOF, FZD10, NUPL1, USP12, UFM1, LECT1, GPC6, ERO1L, BDKRB1, SEMA6D, LACTB, ARIEL CSPG4, AGC1, L0C283824, VASN, WWP2, NOS2A, L0C201181, MSI2, PITPNC1, TGIF, 1552288 at, 1552289 a at, ZNF146, RELB, MIA, ZNF160, SNX5, BMP2, RNF24, HSUP1, MATN4, BIC, RUNX1, LIF, RP4-756G23.1, RPS6KA3, TNMD, RP6-213H19.1, osmosensitive transcription factor TonEBP and a combination thereof. The aforementioned gene products may be delivered as nucleic acid or as protein.
[0044] In other embodiments, any cells to be delivered to an individual in need thereof may be exposed to one or more conditions that provide, facilitate, or enhance therapy for the individual, such as provide, facilitate, or enhance cartilage regeneration and/or repair. In specific embodiments, any cells of the disclosure may be exposed to hypoxia conditions (such as low oxygen tension, for example 5% or less 02), hyperosmotic environment, mechanical strain, or a combination thereof, prior to delivery to the individual, and in other embodiments the cells are alternatively or additionally exposed to hypoxia conditions, mechanical strain, or a combination thereof following in vivo delivery. Examples of mechanical strain include
[0044] In other embodiments, any cells to be delivered to an individual in need thereof may be exposed to one or more conditions that provide, facilitate, or enhance therapy for the individual, such as provide, facilitate, or enhance cartilage regeneration and/or repair. In specific embodiments, any cells of the disclosure may be exposed to hypoxia conditions (such as low oxygen tension, for example 5% or less 02), hyperosmotic environment, mechanical strain, or a combination thereof, prior to delivery to the individual, and in other embodiments the cells are alternatively or additionally exposed to hypoxia conditions, mechanical strain, or a combination thereof following in vivo delivery. Examples of mechanical strain include
13 intermittent hydrostatic pressure, fluid shear stress, low oxygen tension, direct compression, or a combination thereof.
[0045] In specific embodiments, Tie2+ cells are provided to an individual in need thereof. Tie2 may also be referred to as Angiopoietin-1 receptor; CD202B;
hTIE2; p140 TEK;
soluble TIE2 variant 1; soluble TIE2 variant 2; TEK; TEK tyrosine kinase, endothelial; TIE-2;
TIE2; Tunica interna endothelial cell kinase; Tyrosine-protein kinase receptor TEK; Tyrosine-protein kinase receptor TIE-2; VMCM; and VMCM1. Tie2+ cells may be produced, such as by transforming or transfecting a cell in question with a vector comprising a nucleic acid that encodes part or all of the Tie2 protein. Tie2+ cells may be isolated from the individual being treated or from another individual, including another individual of the same or different species.
Tie2+ cells may be isolated using an entity that binds Tie2+, such as a Tie2 antibody or aptamer, for example, and these methods are well known in the art.
[0046] Cells from the nucleus pulposus and/or conditioned medium generated therefrom are provided to the individual, in certain embodiments, and such cells may comprise notochordal cells, small chondrocyte-like cells, or a combination thereof. In addition to cell delivery, other components from the nucleus pulposus may be provided to the individual, such as collagen fibrils and/or aggrecan or any proteoglycan. Any compositions for delivery may be labeled, and compositions may also include antibiotic(s), buffers, salts, media, and so forth.
[0047] In particular aspects, methods of the disclosure include the step of identification of a joint medical condition or disorder or defect, including the joint being a spinal disc. Methods of determining disc defects are known in the art, but in specific embodiments they include CT scan, magnetic resonance imaging, discogram, a combination thereof, and so forth.
In certain cases, when it is determined that a disc has a reduction in notochordal cells, the individual may be in need of therapy of the disclosure.
[0048] Individuals for treatment may have disc issues with unknown cause, or the individuals may be 50 or older than 50, or athletes, for example. In specific embodiments, the individual is in their 20s, 30s, or 40s.
[0049] In particular embodiments, the disclosure encompasses methods for improving the environment of an aged disc by providing a cell blend that comprises a content of cells and numbers of cells that are present or isolated from one or more younger, more virile
[0045] In specific embodiments, Tie2+ cells are provided to an individual in need thereof. Tie2 may also be referred to as Angiopoietin-1 receptor; CD202B;
hTIE2; p140 TEK;
soluble TIE2 variant 1; soluble TIE2 variant 2; TEK; TEK tyrosine kinase, endothelial; TIE-2;
TIE2; Tunica interna endothelial cell kinase; Tyrosine-protein kinase receptor TEK; Tyrosine-protein kinase receptor TIE-2; VMCM; and VMCM1. Tie2+ cells may be produced, such as by transforming or transfecting a cell in question with a vector comprising a nucleic acid that encodes part or all of the Tie2 protein. Tie2+ cells may be isolated from the individual being treated or from another individual, including another individual of the same or different species.
Tie2+ cells may be isolated using an entity that binds Tie2+, such as a Tie2 antibody or aptamer, for example, and these methods are well known in the art.
[0046] Cells from the nucleus pulposus and/or conditioned medium generated therefrom are provided to the individual, in certain embodiments, and such cells may comprise notochordal cells, small chondrocyte-like cells, or a combination thereof. In addition to cell delivery, other components from the nucleus pulposus may be provided to the individual, such as collagen fibrils and/or aggrecan or any proteoglycan. Any compositions for delivery may be labeled, and compositions may also include antibiotic(s), buffers, salts, media, and so forth.
[0047] In particular aspects, methods of the disclosure include the step of identification of a joint medical condition or disorder or defect, including the joint being a spinal disc. Methods of determining disc defects are known in the art, but in specific embodiments they include CT scan, magnetic resonance imaging, discogram, a combination thereof, and so forth.
In certain cases, when it is determined that a disc has a reduction in notochordal cells, the individual may be in need of therapy of the disclosure.
[0048] Individuals for treatment may have disc issues with unknown cause, or the individuals may be 50 or older than 50, or athletes, for example. In specific embodiments, the individual is in their 20s, 30s, or 40s.
[0049] In particular embodiments, the disclosure encompasses methods for improving the environment of an aged disc by providing a cell blend that comprises a content of cells and numbers of cells that are present or isolated from one or more younger, more virile
14 discs. Methods are included for improving the condition of an aged disc in an individual by providing to the individual with the aged disc an effective amount of a cell blend from, or that one would be found in, a disc of a person without the onset of the degenerative process. In particular embodiments, the cell blend comprises fibroblasts; stem cells;
adipocytes; notochordal cells; Tie2+ cells; PRP+ cells; Sox9+ cells; TGFB1+ cells; CTGF+ cells; WISP1+
cells, WISP2+ cells, or a combination thereof. In certain cases, the individual is provided one or more of the following: Tie2 gene product; platelet-rich plasma (PRP); Sox9 gene product; TGFB1 gene product; CTGF gene product; WISP1 gene product; WISP2 gene product; or a combination thereof.
EXAMPLES
[0050] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
[0051] As an example of a method of the disclosure, there is introduction of allogeneic, xenogenic or autologous nucleus pulposus cells and/or conditioned medium generated therefrom, and/or 5ox9 or other genes that aid in the production of cartilage and/or notochordal cells, and/or Tie2+ cells, and/or platelet-rich plasma (PRP). Such delivery will benefit the differentiation process by delivering cells found in abundance in healthy nucleus pulposus, in certain embodiments. The reduction in quantities of 5ox9 or other genes, notochordal cells, and/or Tie2+ play an important role in the onset of degenerative disc disease.
Adding these cells back to a new nucleus created from a fibroblast differentiation, will result in a more robust and vibrant environment for the newly differentiated cells.
Because cartilage typically has low blood flow and access to nutrients, it is considered the most difficult tissue in the body to regenerate. For this reason, other elements may be added to the fibroblast mixture such 5ox9 or other genes, notochordal cells, Tie2+ cells, and/or PRP. Current research suggests the reduction in these cell types may actually be the catalyst or genesis of degenerative disc disease.
REFERENCES
[0052] All patents and publications mentioned in the specification are indicative of the level of those skilled in the art to which the invention pertains. All patents and publications are herein incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.
PATENTS AND PATENT APPLICATIONS
[0053] U.S. Patent No. 7850983, U.S. Patent Publication US
2014/0314726; U.S.
Patent Publication US 2014/0044682; U.S. Patent Publication US 2014/0377231;
and PUBLICATIONS
[00541 Feng, G., L. Li, H. Liu, Y. Song, F. Huang, C. Tu, B. Shen, Q. Gong, T.
Li, L. Liu, J. Zeng, Q. Kong, M. Yi, M. Gupte, P.X. Ma, F. Pei; Hypoxia differentially regulates human nucleus pulposus and annulus fibrosus cell extracellular matrix production in 3D
scaffolds. Osteoarthritis and Cartilage 21(2013) 582-588 [0055] Gruber HE1, Hoelscher GL, Leslie K, Ingram JA, Hanley EN Jr.
Three-dimensional culture of human disc cells within agarose or a collagen sponge:
assessment of proteoglycan production. Biomaterials. 2006 Jan;27(3):371-6. Epub 2005 Aug 11.
[0056] Lijie Zhang, Jerry Hu, Kyriacos A. Athanasiou The Role of Tissue Engineering in Articular Cartilage Repair and Regeneration Crit Rev Biomed Eng. 2009; 37(1-2): 1-57.
[0057] Majumdar MK, Wang E and Morris EA. BMP-2 and BMP-9 promotes chondrogenic differentiation of human multipotential mesenchymal cells and overcomes the inhibitory effect of IL-1. J. Cell. Physiol. 2001(189):275-284.
[0058] Seppa, N.. Cartilage creation. New joint tissue could keep people moving, reducing need for knee or hip replacements. Science News 2012 (189 #3):22.
[0059] Tang, X., William J. Richardson, Robert D. Fitch, Christopher R. Brown, Robert E. Isaacs, A new non-enzymatic method for isolating human intervertebral disc cells preserves the phenotype of nucleus pulposus cells Jun ChenCytotechnology (2014) 66:979-986.
[0060] Wang SZ1, Rui YF, Lu J, Wang C. Cell and molecular biology of intervertebral disc degeneration: current understanding and implications for potential therapeutic strategies. Cell Prolif. 2014 Oct;47(5):381-90. doi: 10.1111/cpr.12121. Epub 2014 Aug 11.
[0061] Zaslav K. Cole B. et al: The American Journal of Sports Medicine.
2009;37(1):42-55.
[0062] Zaslav K. Cole B. et al. A Prospective Study of Autologous Chondrocyte Implantation in Patients Who Failed Prior Treatments for Articular Cartilage The American Journal of Sports Medicine. 2009;37(1):42-55.
[0063] Although the present invention and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims. Moreover, the scope of the present application is not intended to be limited to the particular embodiments of the process, machine, manufacture, composition of matter, means, methods and steps described in the specification. As one of ordinary skill in the art will readily appreciate from the disclosure of the present invention, processes, machines, manufacture, compositions of matter, means, methods, or steps, presently existing or later to be developed that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein may be utilized according to the present invention.
Accordingly, the appended claims are intended to include within their scope such processes, machines, manufacture, compositions of matter, means, methods, or steps.
adipocytes; notochordal cells; Tie2+ cells; PRP+ cells; Sox9+ cells; TGFB1+ cells; CTGF+ cells; WISP1+
cells, WISP2+ cells, or a combination thereof. In certain cases, the individual is provided one or more of the following: Tie2 gene product; platelet-rich plasma (PRP); Sox9 gene product; TGFB1 gene product; CTGF gene product; WISP1 gene product; WISP2 gene product; or a combination thereof.
EXAMPLES
[0050] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
[0051] As an example of a method of the disclosure, there is introduction of allogeneic, xenogenic or autologous nucleus pulposus cells and/or conditioned medium generated therefrom, and/or 5ox9 or other genes that aid in the production of cartilage and/or notochordal cells, and/or Tie2+ cells, and/or platelet-rich plasma (PRP). Such delivery will benefit the differentiation process by delivering cells found in abundance in healthy nucleus pulposus, in certain embodiments. The reduction in quantities of 5ox9 or other genes, notochordal cells, and/or Tie2+ play an important role in the onset of degenerative disc disease.
Adding these cells back to a new nucleus created from a fibroblast differentiation, will result in a more robust and vibrant environment for the newly differentiated cells.
Because cartilage typically has low blood flow and access to nutrients, it is considered the most difficult tissue in the body to regenerate. For this reason, other elements may be added to the fibroblast mixture such 5ox9 or other genes, notochordal cells, Tie2+ cells, and/or PRP. Current research suggests the reduction in these cell types may actually be the catalyst or genesis of degenerative disc disease.
REFERENCES
[0052] All patents and publications mentioned in the specification are indicative of the level of those skilled in the art to which the invention pertains. All patents and publications are herein incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.
PATENTS AND PATENT APPLICATIONS
[0053] U.S. Patent No. 7850983, U.S. Patent Publication US
2014/0314726; U.S.
Patent Publication US 2014/0044682; U.S. Patent Publication US 2014/0377231;
and PUBLICATIONS
[00541 Feng, G., L. Li, H. Liu, Y. Song, F. Huang, C. Tu, B. Shen, Q. Gong, T.
Li, L. Liu, J. Zeng, Q. Kong, M. Yi, M. Gupte, P.X. Ma, F. Pei; Hypoxia differentially regulates human nucleus pulposus and annulus fibrosus cell extracellular matrix production in 3D
scaffolds. Osteoarthritis and Cartilage 21(2013) 582-588 [0055] Gruber HE1, Hoelscher GL, Leslie K, Ingram JA, Hanley EN Jr.
Three-dimensional culture of human disc cells within agarose or a collagen sponge:
assessment of proteoglycan production. Biomaterials. 2006 Jan;27(3):371-6. Epub 2005 Aug 11.
[0056] Lijie Zhang, Jerry Hu, Kyriacos A. Athanasiou The Role of Tissue Engineering in Articular Cartilage Repair and Regeneration Crit Rev Biomed Eng. 2009; 37(1-2): 1-57.
[0057] Majumdar MK, Wang E and Morris EA. BMP-2 and BMP-9 promotes chondrogenic differentiation of human multipotential mesenchymal cells and overcomes the inhibitory effect of IL-1. J. Cell. Physiol. 2001(189):275-284.
[0058] Seppa, N.. Cartilage creation. New joint tissue could keep people moving, reducing need for knee or hip replacements. Science News 2012 (189 #3):22.
[0059] Tang, X., William J. Richardson, Robert D. Fitch, Christopher R. Brown, Robert E. Isaacs, A new non-enzymatic method for isolating human intervertebral disc cells preserves the phenotype of nucleus pulposus cells Jun ChenCytotechnology (2014) 66:979-986.
[0060] Wang SZ1, Rui YF, Lu J, Wang C. Cell and molecular biology of intervertebral disc degeneration: current understanding and implications for potential therapeutic strategies. Cell Prolif. 2014 Oct;47(5):381-90. doi: 10.1111/cpr.12121. Epub 2014 Aug 11.
[0061] Zaslav K. Cole B. et al: The American Journal of Sports Medicine.
2009;37(1):42-55.
[0062] Zaslav K. Cole B. et al. A Prospective Study of Autologous Chondrocyte Implantation in Patients Who Failed Prior Treatments for Articular Cartilage The American Journal of Sports Medicine. 2009;37(1):42-55.
[0063] Although the present invention and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims. Moreover, the scope of the present application is not intended to be limited to the particular embodiments of the process, machine, manufacture, composition of matter, means, methods and steps described in the specification. As one of ordinary skill in the art will readily appreciate from the disclosure of the present invention, processes, machines, manufacture, compositions of matter, means, methods, or steps, presently existing or later to be developed that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein may be utilized according to the present invention.
Accordingly, the appended claims are intended to include within their scope such processes, machines, manufacture, compositions of matter, means, methods, or steps.
Claims (30)
1. A method of generating chondrocytes or chondrocyte-like cells for an individual, comprising the step of providing to a degenerated disc of an individual an effective amount of one or more components from the nucleus pulposus (NP) of the same individual or another individual from the same or different species.
2. The method of claim 1, wherein components from the NP comprise notochordal cells, notochordal cell conditioned media, small chondrocyte-like cells, collagen fibrils, proteoglycans, and/or aggrecan.
3. The method of claim 1 or 2, wherein one or more therapeutic agents are provided to the degenerated disc of the individual.
4. The method of claim 1, 2, or 3, wherein the one or more therapeutic agents comprise nucleic acid, peptide, protein, small molecule, or a combination thereof.
5. The method of any one of claims 1-4, comprising the step of providing to the individual one or more compositions comprising an effective amount of one or more of the following:
a) fibroblasts;
b) notochordal cells;
c) Tie2+ cells;
d) Tie2 gene product;
e) platelet-rich plasma (PRP);
f) Sox9 gene product;
g) transforming growth factor beta-1 (TGFB 1);
h) connective tissue growth factor (CTGF);
i) WNT1-inducible-signaling pathway protein 1 (WISP1), and/or j) WISP2.
a) fibroblasts;
b) notochordal cells;
c) Tie2+ cells;
d) Tie2 gene product;
e) platelet-rich plasma (PRP);
f) Sox9 gene product;
g) transforming growth factor beta-1 (TGFB 1);
h) connective tissue growth factor (CTGF);
i) WNT1-inducible-signaling pathway protein 1 (WISP1), and/or j) WISP2.
6. The method of any one of claims 1-5, wherein cells of the NP are modified ex vivo prior to providing them to the individual.
7. The method of claim 5, wherein the fibroblasts, notochordal cells, and/or Tie2+ cells are modified ex vivo.
8. The method of any one of claims 1-7, wherein cells are exposed to hypoxia, mechanical strain, or a combination thereof prior to the providing step.
9. The method of claim 8, wherein the mechanical strain comprises intermittent hydrostatic pressure, fluid shear stress, low oxygen tension, direct compression, or a combination thereof.
10. The method of any one of claims 1-9, wherein the Tie2 gene product is produced by one or more of the cells.
11. The method of any one of claims 1-9, wherein the Sox9 gene product is produced by one or more of the cells.
12. The method of claim 3 or 4, wherein the agent comprises a gene product selected from the group consisting of COL1A1, COL1A2, COL2A1, COL3A1, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6, COL5A1, COL5A2, COL5A3, COL6A1, COL6A2, COL6A3, COL6A4, COL6A5, COL7A1, COL8A1, COL8A2, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1, COL11A2, COL12A1, COL13A1, COL14A1, COL15A1, COL16A1, COL17A1, COL18A1, COL19A1, COL20A1, COL21A1, COL22A1, COL23A1, COL24A1, COL25A1, COL26A1, COL27A1, COL28A1, Gata4, Mef2C, Tbx5, Sox5, Sox6, 5ox9, FGFR2, VEGF, MMP14, forkhead, CD10, MMP13, WNT11, BAPX1, IL-1R1, IGFBP5, MMP16, BMP2, ALK1, BMP5, IGF1, MMP13, ADAMTS5, BCL10, MCOLN2, LRRC8C, PTGFR, RLF, MATN1, PDPN, TNFRSF18, ITGA10, THBS3, SCYL1BP1, KCNT2, 244533 at, ARF1, 222348 at, SLC4A5, HSPC159, RHOQ, MATN3, SULT1C2, 236289 at, BCL2L11, F1116008, KLF7, NRP2, SERPINE2, FN1, B3GNT7, ADAMTS9, ANKRD28, GALNTL2, IRAK2, SETD5, FNDC3B, B3GNT5, CYTL1, IBSP, 229221 at, PET112L, EDNRA, 1563414 at, OSMR, C1QTNF3, ZFYVE16, 225611_at, MAST4, EDIL3, 230204_at, 230895_at, HAPLN1, PDLIM4, cr5q35 SQSTM1, SCUBE3, CMAH, 236685_at, BMP6, ULBP2, LRP11, SOD2, SYNJ2, WTAP, HIG2, KIAA1718, FAM62B, UBE3C, TNFRSF10D, SLC25A37, ChGn, RB1CC1, C8orf72, EIF2C2, HAS2, TRPS1, WISP1, 235821_at, PTK2, ZCCHC7, RPS6, GLIS3, SLC28A3, 1555841_at, MGC17337, EDG2, 229242_at, ITGB1, C10orf49, YME1L1, AKR1C2, CHST3, LOXL4, SFXN3, 228910_at, CD44, FOSL1, RELA, MMP12, MMP13, MMP3, KIAA0999, ASAM, LOC399959, ETNK1, SOX5, CHST11, ATF1, SRGAP1, DSPG3, LOC338758, KIAA0701, SLC41A2, RHOF, FZD10, NUPL1, USP12, UFM1, LECT1, GPC6, ERO1L, BDKRB1, SEMA6D, LACTB, ARIH1, CSPG4, AGC1, LOC283824, VASN, WWP2, NOS2A, LOC201181, MSI2, PITPNC1, TGIF, 1552288_at, 1552289_a_at, ZNF146, RELB, MIA, ZNF160, SNX5, BMP2, RNF24, HSUP1, MATN4, BIC, RUNX1, LIF, RP4-756G23.1, RPS6KA3, TNMD, RP6-213H19.1, and a combination thereof.
13. The method of any one of claims 1-12, wherein the cells are autologous, allogeneic, or xenogeneic in relation to the individual.
14. The method of any one of claims 1-13, wherein the method further comprises detection of the degenerated disc.
15. The method of claim 14, wherein the degenerated disc is detected by measuring the level of notochord cells in the NP of a disc in the individual suspected of being degenerated.
16. The method of claim 14, wherein the degenerated disc is detected structurally or non-structurally.
17. The method of claim 16, wherein non-structural detection comprises by biochemical or molecular means.
18. The method of any one of claims 1-17, wherein the individual is also provided an effective amount of fibroblasts, stem cells, and/or adipocytes.
19. A method of repairing and/or regenerating cartilage in a spinal disc of an individual in need thereof, comprising the steps of:
a) providing fibroblasts, stem cells, adipocytes, or a combination thereof to the disc of the individual;
b) providing one or more components from the nucleus pulposus (NP) to the disc of the individual; and c) providing one or more of the following to the disc of the individual:
1) Tie2+ cells;
2) Tie2 gene product;
3) platelet-rich plasma (PRP);
4) PRP+ cells;
5) Sox9 gene product;
6) Sox9+ cells 7) TGFB1 gene product;
8) TGFB1+ cells;
9) CTGF gene product;
10) CTGF+ cells;
11) WISP1 gene product;
12) WISP1+ cells, 13) WISP2 gene product; and/or 14) WISP2+ cells.
a) providing fibroblasts, stem cells, adipocytes, or a combination thereof to the disc of the individual;
b) providing one or more components from the nucleus pulposus (NP) to the disc of the individual; and c) providing one or more of the following to the disc of the individual:
1) Tie2+ cells;
2) Tie2 gene product;
3) platelet-rich plasma (PRP);
4) PRP+ cells;
5) Sox9 gene product;
6) Sox9+ cells 7) TGFB1 gene product;
8) TGFB1+ cells;
9) CTGF gene product;
10) CTGF+ cells;
11) WISP1 gene product;
12) WISP1+ cells, 13) WISP2 gene product; and/or 14) WISP2+ cells.
20. The method of claim 19, wherein the one or more components of the NP
comprise notochordal cells, small chondrocyte-like cells, collagen fibrils, and/or aggrecan.
comprise notochordal cells, small chondrocyte-like cells, collagen fibrils, and/or aggrecan.
21. The method of claim 19 or 20, wherein step a) occurs prior to steps b) and/or c).
22. The method of any one of claims 19-21, wherein the individual is also provided an effective amount of fibroblasts, stem cells, and/or adipocytes.
23. A method of repairing and/or regenerating cartilage in a spinal disc of an individual in need thereof, comprising the steps of:
combining one or more of the compositions listed in a), b) and/or c) with another one or more of the compositions listed in a), b), and/or c) to produce a mixture:
a) fibroblasts, stem cells, adipocytes, or a combination thereof;
b) one or more components from the nucleus pulposus (NP);
c) one or more of the following:
1) Tie2+ cells;
2) Tie2 gene product;
3) platelet-rich plasma (PRP);
4) PRP+ cells;
5) Sox9 gene product; and 6) Sox9+ cells;
7) TGFB1 gene product;
8) TGFB1+ cells;
9) CTGF gene product;
10) CTGF+ cells;
11) WISP1 gene product;
12) WISP1+ cells, 13) WISP2 gene product; and/or 14) WISP2+ cells; and providing the mixture to the individual.
combining one or more of the compositions listed in a), b) and/or c) with another one or more of the compositions listed in a), b), and/or c) to produce a mixture:
a) fibroblasts, stem cells, adipocytes, or a combination thereof;
b) one or more components from the nucleus pulposus (NP);
c) one or more of the following:
1) Tie2+ cells;
2) Tie2 gene product;
3) platelet-rich plasma (PRP);
4) PRP+ cells;
5) Sox9 gene product; and 6) Sox9+ cells;
7) TGFB1 gene product;
8) TGFB1+ cells;
9) CTGF gene product;
10) CTGF+ cells;
11) WISP1 gene product;
12) WISP1+ cells, 13) WISP2 gene product; and/or 14) WISP2+ cells; and providing the mixture to the individual.
24. The method of claim 23, wherein the mixture is generated in vitro.
25. The method of claim 23, wherein the mixture is generated in vivo.
26. The method of any one of claims 23-25, wherein the mixture is delivered to the individual by injection, by insertion via open incision, by catheter, or a combination thereof.
27. The method of any one of claims 23-26, wherein the individual is also provided an effective amount of fibroblasts, stem cells, and/or adipocytes.
28. A method of improving the condition of an aged disc in an individual by providing to the individual with the aged disc an effective amount of a cell blend from, or that one would be found in, a disc of a person without the onset of the degenerative process.
29. The method of claim 28, wherein the cell blend comprises fibroblasts;
stem cells; adipocytes; notochordal cells; Tie2+ cells; PRP+ cells; Sox9+
cells;
TGFB1+ cells; CTGF+ cells; WISP1+ cells, WISP2+ cells, or a combination thereof.
stem cells; adipocytes; notochordal cells; Tie2+ cells; PRP+ cells; Sox9+
cells;
TGFB1+ cells; CTGF+ cells; WISP1+ cells, WISP2+ cells, or a combination thereof.
30. The method of claim 28 or 29, wherein the individual is provided one or more of the following: Tie2 gene product; platelet-rich plasma (PRP); Sox9 gene product; TGFB1 gene product; CTGF gene product; WISP1 gene product; WISP2 gene product; or a combination thereof.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662278635P | 2016-01-14 | 2016-01-14 | |
US62/278,635 | 2016-01-14 | ||
US201662413587P | 2016-10-27 | 2016-10-27 | |
US62/413,587 | 2016-10-27 | ||
PCT/US2017/013449 WO2017123951A1 (en) | 2016-01-14 | 2017-01-13 | Cellular blend for the regeneration of chondrocytes or cartilage type cells |
Publications (1)
Publication Number | Publication Date |
---|---|
CA3011306A1 true CA3011306A1 (en) | 2017-07-20 |
Family
ID=59311534
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA3011306A Pending CA3011306A1 (en) | 2016-01-14 | 2017-01-13 | Cellular blend for the regeneration of chondrocytes or cartilage type cells |
Country Status (8)
Country | Link |
---|---|
US (1) | US20190022145A1 (en) |
EP (1) | EP3402534A4 (en) |
JP (2) | JP2019501943A (en) |
CN (1) | CN108697812A (en) |
AU (2) | AU2017207445B2 (en) |
CA (1) | CA3011306A1 (en) |
HK (1) | HK1256160A1 (en) |
WO (1) | WO2017123951A1 (en) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3402542B1 (en) | 2016-01-11 | 2022-03-09 | Technische Universiteit Eindhoven | Notochordal cell matrix as a stimulant for intervertebral disc regeneration |
CN110337490A (en) * | 2017-01-11 | 2019-10-15 | 脊核细胞有限责任公司 | Enhance the method for fibroblast therapeutic activity |
KR102588627B1 (en) | 2017-03-08 | 2023-10-16 | 김성진 | Composition for preparing extracellular matrix using MAST4 gene and method for preparing the same |
KR20190024727A (en) | 2017-08-29 | 2019-03-08 | 중앙대학교 산학협력단 | Composition for cartilage regeneration comprising HAPLN1 |
WO2019045451A1 (en) * | 2017-08-29 | 2019-03-07 | 중앙대학교 산학협력단 | Cartilage regeneration composition containing hapln1 as active ingredient |
US11779609B2 (en) * | 2018-01-30 | 2023-10-10 | Technische Universiteit Eindhoven | Notochordal cell matrix as a bioactive lubricant for the osteoarthritic joint |
CN109136169A (en) * | 2018-08-09 | 2019-01-04 | 上海交通大学医学院附属第九人民医院 | A kind of skin fibroblasts are changed into the system and its application method of artificial intervertebral disk |
AU2019431082B2 (en) | 2019-02-28 | 2022-12-15 | Haplnscience inc. | Composition, for preventing, relieving or treating cartilage-related diseases or symptoms, comprising HAPLN1 |
JP6712740B1 (en) * | 2019-03-25 | 2020-06-24 | 学校法人東海大学 | Method for culturing cell population containing Tie2-positive stem/progenitor cells and use thereof |
EP3947643A1 (en) * | 2019-03-29 | 2022-02-09 | Tokai University Educational System | Differentiation inducer containing nucleus pulposus cell master regulator transcription factors, method for producing induced nucleus pulposus cells, and use of induced nucleus pulposus cells |
CN112877364B (en) * | 2019-11-29 | 2023-07-28 | 中国医学科学院药物研究所 | Reprogramming induction scheme for direct conversion of subchondral bone cells to articular cartilage cells |
WO2023212637A1 (en) * | 2022-04-29 | 2023-11-02 | CryoHeart Laboratories, Inc. | Systems, methods, and devices of exosome delivery for filling bone fracture voids |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1989289B1 (en) * | 2006-02-07 | 2017-01-04 | Spinalcyte, LLC | Methods and compositions for repair of cartilage using an in vivo bioreactor |
EP2034010A1 (en) * | 2007-08-30 | 2009-03-11 | Omrix Biopharmaceuticals Ltd. | Compositions suitable for repair and/or treatment of injured spinal tissue |
WO2010088775A1 (en) * | 2009-02-06 | 2010-08-12 | University Health Network | Methods and uses of hypoxic compartment cells |
US20130078222A1 (en) * | 2010-03-30 | 2013-03-28 | Tokai University Educational System | Intervertebral Disc Nucleus Pulposus Stem Cell/Progenitor Cell, The Cultivation Method And Intended Use Thereof |
WO2013070880A1 (en) * | 2011-11-09 | 2013-05-16 | Spinalcyte, Llc | Fibroblasts for treatment of degenerative disc disease |
WO2014026012A2 (en) * | 2012-08-10 | 2014-02-13 | Advanced Medical Technologies Llc | Generation of cartilage ex vivo from fibroblasts |
SG10201707546SA (en) * | 2013-03-15 | 2017-10-30 | Discgenics Inc | Isolated discogenic cells, methods of using, and methods of preparing same from mammalian tissue |
EP3011015B1 (en) * | 2013-06-19 | 2021-02-24 | Spinalcyte, LLC | Adipose cells for chondrocyte applications |
CA2923857A1 (en) * | 2013-09-09 | 2015-03-12 | Figene, Llc | Gene therapy for the regeneration of chondrocytes or cartilage type cells |
-
2017
- 2017-01-13 US US16/068,096 patent/US20190022145A1/en active Pending
- 2017-01-13 AU AU2017207445A patent/AU2017207445B2/en active Active
- 2017-01-13 EP EP17739050.7A patent/EP3402534A4/en active Pending
- 2017-01-13 CN CN201780011692.1A patent/CN108697812A/en active Pending
- 2017-01-13 CA CA3011306A patent/CA3011306A1/en active Pending
- 2017-01-13 JP JP2018536724A patent/JP2019501943A/en active Pending
- 2017-01-13 WO PCT/US2017/013449 patent/WO2017123951A1/en active Application Filing
-
2018
- 2018-11-28 HK HK18115243.3A patent/HK1256160A1/en unknown
-
2021
- 2021-10-08 JP JP2021165865A patent/JP2022000481A/en active Pending
-
2024
- 2024-02-15 AU AU2024200985A patent/AU2024200985A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
AU2024200985A1 (en) | 2024-03-14 |
WO2017123951A8 (en) | 2018-08-16 |
EP3402534A4 (en) | 2019-09-18 |
WO2017123951A1 (en) | 2017-07-20 |
CN108697812A (en) | 2018-10-23 |
EP3402534A1 (en) | 2018-11-21 |
AU2017207445A1 (en) | 2018-07-19 |
JP2022000481A (en) | 2022-01-04 |
AU2017207445B2 (en) | 2023-12-07 |
US20190022145A1 (en) | 2019-01-24 |
HK1256160A1 (en) | 2019-09-13 |
JP2019501943A (en) | 2019-01-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2017207445B2 (en) | Cellular blend for the regeneration of chondrocytes or cartilage type cells | |
Huang et al. | A functional biphasic biomaterial homing mesenchymal stem cells for in vivo cartilage regeneration | |
Silva-Correia et al. | Tissue engineering strategies applied in the regeneration of the human intervertebral disk | |
AU2014317861B2 (en) | Gene therapy for the regeneration of chondrocytes or cartilage type cells | |
ES2822909T3 (en) | Dermal fibroblasts for the treatment of degenerative disc disease | |
JP7084963B2 (en) | Adipocytes for chondrocyte application | |
JP2010537968A (en) | Compositions suitable for the treatment of spinal cord diseases, disorders or symptoms | |
WO2010065854A1 (en) | Methods and compositions to facilitate repair of avascular tissue | |
JP2020000891A (en) | Generation of cartilage ex vivo from fibroblasts | |
Feng et al. | Hypoxia promotes nucleus pulposus phenotype in 3D scaffolds in vitro and in vivo | |
Akyuva et al. | Delivering growth factors through a polymeric scaffold to cell cultures containing both nucleus pulposus and annulus fibrosus | |
Zheng et al. | Core-shell oxygen-releasing fibers for annulus fibrosus repair in the intervertebral disc of rats | |
Sukri et al. | The feasibility of using human primary chondrocytes derived from osteoarthritic patients overexpressed with SOX9 seeded on PLGA-fibrin hybrid scaffolds for cartilage engineering | |
Bai et al. | Treatments for intervertebral discs degeneration by stem cells transplantation: a therapeutic potential comparison between bone marrow stem cells and adipose-derived stem cells | |
Schwab | Development of an osteochondral cartilage defect model | |
Wang et al. | Injectable Hybrid Inorganic Nanoscaffold-templated Rapid Stem Cell Assembly for Cartilage Repair | |
Nery | Cellular and Mechano-Active Material Approaches to Improve Disc Repair after Herniation | |
Christiani | Bioadhesive hydrogel composite cell carrier for the repair of the degenerated intervertebral disc | |
Wang et al. | Biological Characterization of a Glutaraldehyde Cross-Linked Type II Collagen Scaffold for Nucleus Pulposus Differentiation of Human Mesenchymal Stem Cells | |
ES2414285T3 (en) | Composition and procedures for the production of biological tissues and tissue constructions | |
Shi | Development of experimental protocols for a heterogeneous bioscaffold-chondrocyte construct with application to a tissue engineered spinal disc | |
Hughes | Mesenchymal Stem Cell Differentiation to Nucleus Pulposus-like Cells, in Chitosan Glycerophosphate for the Repair of the Degenerate Intervertebral Disc | |
Francisco | Laminin-Functionalized Polyethylene Glycol Hydrogels for Nucleus Pulposus Regeneration | |
Churchill | MENISCAL TISSUE ENGINEERING USING ELECTROSPUN NATURAL/COLLAGEN: COMPARISON OF DIFFERENT CELL SOURCES. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request |
Effective date: 20211217 |
|
EEER | Examination request |
Effective date: 20211217 |
|
EEER | Examination request |
Effective date: 20211217 |
|
EEER | Examination request |
Effective date: 20211217 |
|
EEER | Examination request |
Effective date: 20211217 |